Plant-Derived Bioactive Compounds for Cancer Therapy: Mechanisms, Clinical Evidence, and Translational Challenges

According to estimates from the Global Cancer Observatory (GLOBOCAN), the number of new cancer cases worldwide in 2020 was 19.3 million (Sung, Hyuna et al.2021). India was ranked as the third-highest country in terms of incident cancer cases, following China and the United States of America. GLOBOCAN has projected that the number of cancer cases in India will reach 2.08 million by 2040, representing a significant increase of 57.5 percent compared to 2020.(Ferlay, Jacques et al. 2020). The search for effective and safe treatments for cancer remains a global priority, as this devastating disease continues to impact millions of lives worldwide. In recent years, there has been a growing interest in exploring natural sources, such as medicinal plants, for potential anticancer agents. Medicinal plants have a long history of use in traditional medicine systems and are known to contain a wide array of bioactive compounds with diverse therapeutic properties. The scientific and research community is increasingly focusing on naturally-derived compounds due to their perceived lower toxic side effects in comparison to current treatments like chemotherapy. The Plant Kingdom produces naturally occurring secondary metabolites which are being investigated for their anticancer activities leading to the development of new clinical drugs. (Greenwell et al., 2015).

Among the bioactive compounds derived from medicinal plants, botanical derivatives have gained significant attention due to their potential anticancer properties. These derivatives, including alkaloids, flavonoids, terpenoids, polyphenols, and lectins, have demonstrated promising effects against various types of cancers (Nasim et al. 2022). Understanding the mechanisms underlying their anticancer activities is crucial for harnessing their therapeutic potential. Critical regulatory pathways, including the MAPK pathway, PI3K/AKT/mTOR signaling, and the Wnt/β-catenin signaling pathway, hold vital significance in governing signal transduction and fundamental biological processes such as cell proliferation, apoptosis, and metabolism, among others. The intricate regulatory mechanisms and biological functions of these signaling pathways are pivotal in numerous human cancers. Despite promising outcomes from combining various therapeutic approaches, several challenges persist in devising an effective antitumoral treatment that specifically targets tumoral cells (Fu et al., 2022). Natural plant extracts and derivatives have been reported to impact multiple oncological pathways that are related to apoptosis, angiogenesis, MAPK, cell cycle progression/proliferation, reprogrammed metabolisms, and epigenetics. Identification of these botanic derivative-impacted oncological pathways will help design or modify botanical lead compounds to generate potent anticancer drugs with minimal side-effects.

Botanical derivatives exhibit multifaceted mechanisms of action against cancer cells. Some compounds induce apoptosis, a programmed cell death mechanism that eliminates damaged or abnormal cells. Others disrupt cell cycle progression, leading to cell cycle arrest and inhibition of uncontrolled cell growth. Additionally, certain botanical derivatives inhibit angiogenesis, the process by which tumors develop their blood supply, thereby impeding tumor growth and metastasis (Banerjee et al 2022). Moreover, botanical derivatives can modulate signalling pathways involved in cancer development and progression. By targeting these pathways, they can interfere with key cellular processes, such as cell proliferation, migration, and invasion. Furthermore, botanical derivatives have been shown to enhance the immune system's response to cancer cells, promoting immune-mediated cytotoxicity and suppressing tumor growth.

Plant-derived drugs offer desirable attributes for cancer treatment owing to their natural origin and easy availability. These compounds have played a crucial role in addressing various types of cancer effectively. Notable examples of such agents include Vinblastine, Vincristine, Docetaxel, Etoposide (derived from Epipodophyllotoxin), Paclitaxel (Taxol), Flavonoids from Ginkgo biloba, Curcuma longa, Berberine, among others. Additionally, marine and microbiological organisms have also provided a diverse array of bioactive agents with significant therapeutic potential for anticancer treatments, complementing the efficacy of herbal natural products. Prominent examples of these drugs include trabectedin, dolastin, halichondrin, anthracyclines, and enediynes (Deep et al., 2023). The wide range of anticancer mechanisms exhibited by botanical derivatives makes them an intriguing area of research and holds promise for the development of novel therapeutic interventions. Furthermore, their natural origin offers potential advantages, such as reduced toxicity and better tolerability compared to synthetic drugs. However, extensive scientific investigations, including preclinical and clinical studies, are essential to fully understand their efficacy, safety, and potential interactions with conventional cancer treatments. (Saklani & Kutty, 2008)

In this article, we aim to provide a narrative overview of the anticancer properties and mechanisms of action of botanical derivatives derived from medicinal plants. By examining the current body of scientific literature, we will delve into the diverse classes of compounds and their specific effects on cancer cells. Understanding the mechanisms by which botanical derivatives exert their anticancer activities will not only contribute to our knowledge of natural therapeutics but also pave the way for the development of targeted and personalized cancer treatments.

By exploring the potential of botanical derivatives as anticancer agents, we hope to contribute to the growing body of evidence supporting the use of natural compounds in cancer therapy. Ultimately, the integration of traditional medicine and modern scientific approaches can provide new avenues for improving cancer treatment outcomes and enhancing the quality of life for patients.

2. LITERATURE SEARCH STRATEGY

This article is a narrative review, not a systematic review or meta-analysis. A selective literature search was conducted using PubMed and Google Scholar to identify publications relevant to plant-derived bioactive compounds and cancer. Search concepts included medicinal plants, plant extracts, phytochemicals, anticancer activity, apoptosis, cell-cycle arrest, angiogenesis, tumour growth, signalling pathways, phytochemical isolation, and clinical trials. English-language publications available up to March 2023 were considered.

Publications were considered relevant when they addressed phytochemical composition, extraction or characterization, anticancer activity in cellular or animal models, mechanisms of action, clinical development, safety, or limitations affecting translation. The review also considered selected established anticancer medicines derived from natural products to provide context for natural-product drug discovery. This selective approach was intended to provide a broad overview of key themes rather than a reproducible exhaustive search.

Because a complete database-specific search strategy, duplicate-removal log, formal screening flow, and structured risk-of-bias assessment were not documented, the article should not be interpreted as a systematic or scoping review. Statements about clinical evidence should be checked against primary trial records and publications before submission.

3. PLANT-DERIVED BIOACTIVE COMPOUNDS AS ANTICANCER AGENTS

Bioactive principles found in medicinal plants are of significant interest due to their potential therapeutic applications. These bioactive compounds, also known as secondary metabolites, are derived from primary metabolites and play essential roles in the survival and defense mechanisms of plants against pathogens and herbivores. (Newman & Cragg, 2016). Additionally, they exhibit diverse pharmacological effects in mammalian systems, making them valuable sources for drug discovery and development.

Several classes of bioactive principles have been identified in medicinal plants, including alkaloids, flavonoids, terpenoids, phenolic compounds, and glycosides, among others. These compounds have demonstrated various biological activities, such as antioxidant, anti-inflammatory, antimicrobial, anticancer, and neuroprotective properties. In recent decades, researchers have directed their efforts towards drug discovery using herbal medicines or botanical sources, which are an essential part of complementary and alternative medicine (CAM) therapy (Pan et al., 2013).

3.1. Polyphenols

Polyphenols are a group of organic compounds with over 10,000 members that share a three-membered flavan ring system. These natural compounds are known for their advantageous properties, including scavenging free radicals, reducing oxidative stress, and modulating inflammation. In this context, the role of polyphenols, particularly curcumin, resveratrol, and epigallocatechin gallate (EGCG), in addressing various aspects of cancer drug resistance is discussed (Maleki et al., 2022). Resveratrol, found in peanuts, grapes, and red wine, and gallacatechins from green tea, exhibit antioxidative effects, contributing to overall health improvement and reducing the risk of cancer. Moreover, polyphenols trigger apoptosis in cancer cells by regulating copper ion mobilization, causing DNA fragmentation, and interfering with cancer-related proteins, such as Tumour Necrosis Factor (TNF) (Niedzwiecki et al., 2016).

3.2. Flavonoids

Flavonoids, which are a subclass of polyphenolic compounds, constitute a wide family of plant secondary metabolites with diverse structures and physiological activities. They can be categorized into several classes, such as flavones (e.g., flavone, apigenin, and luteolin), flavonols (e.g., quercetin, kaempferol, myricetin, and fisetin), flavanones (e.g., flavanone, hesperetin, and naringenin), and others. Flavonoids share a benzo-γ-pyrone structure and are widely distributed in plants (Kumar et al., 2013). Extracted from various plants, flavonoids display potent anticancer effects against different types of cancer, including hepatoma, cervical carcinoma, and breast cancer. These compounds induce apoptosis through intrinsic and extrinsic signaling pathways, disrupt mitochondrial function, and interfere with proteins involved in cancer cell survival, proliferation, and angiogenesis (Kopustinskiene et al., 2020).

3.3. Alkaloids

Alkaloids are a remarkably diverse group of compounds characterized by cyclic structures containing at least one basic nitrogen atom. These compounds are widely distributed in the plant kingdom, with significant presence in plants belonging to families like Leguminosae, Menispermaceae, Ranunculaceae, Loganiaceae, and Papaveraceae (Benyhe, 1994; Li et al., 2007; Huang et al., 2007). Many well-known chemotherapeutic agents, such as camptothecin, vincristine, vinblastine, berberine, sanguinarine, evodiamine, piperine, matrine, and tetrandrine, are classified as alkaloids. They have garnered considerable attention for their ability to regulate various mechanistic pathways involved in proliferation, cell cycle, and metastasis. Notably, vincristine and vinblastine have a historical significance in cancer treatment and are actively used in managing acute lymphoblastic leukemia (Mondal et al., 2019). Some antitumor drugs used clinically, including vincristine, vinblastine, and paclitaxel, have natural origins as alkaloids.

3.4. Terpenoids

Terpenoids, the largest and most diverse group of naturally occurring phytoconstituents, are responsible for imparting fragrance, taste, and pigmentation to plants. Their classification is based on the number of isoprene units they contain, which serve as the building blocks for terpenoids. Isoprene is a gaseous hydrocarbon with a molecular formula of C5H8 (Kamran et al., 2022). Terpenoids, composed of these isoprenoid units, represent one of the most extensive groups of natural products, with over 40,000 individual compounds discovered so far, and new ones continue to be identified each year (Sacchettini et al., 1997; Peñuelas et al., 2005; Withers et al., 2007). While most terpenoids originate from plants, they are also synthesized by other organisms, such as bacteria and yeast, as part of their primary or secondary metabolism. The classification of terpenoids includes various classes, such as monoterpenes (e.g., carvone, geraniol, d-limonene, and perillyl alcohol), diterpenes (e.g., retinol and trans-retinoic acid), triterpenes (e.g., betulinic acid, lupeol, oleanic acid, and ursolic acid), and tetraterpenes (e.g., α-carotene, β-carotene, lutein, and lycopene) (Rabi et al., 2009).

3.5. Brassinosteroids

Brassinosteroids (BRs), which are naturally occurring compounds in plants, play vital roles in hormonal signaling, growth regulation, and stress responses. Among them, 28-homocastasterone and 24-epibrassinolide have shown remarkable anticancer effects against multiple cancer cell lines, including T-lymphoblastic leukemia, multiple myeloma, and various carcinoma cell lines. These BRs interact with crucial proteins involved in breast and prostate cancers, such as estrogen receptor, epidermal growth factor receptor, and androgen receptor, leading to growth inhibition and induction of apoptosis. Notably, BRs exhibit distinct responses in normal and cancer cells, making them promising selective agents against cancer cells (Ma et al., 2022).

3.6. Cardiac Glycosides

Cardiac glycosides (CGs) are natural compounds widely utilized to treat various cardiac conditions and have more recently gained recognition as potential antitumor agents. They act as ligands for Na/K-ATPase, which is a promising drug target in cancer treatment (Schneider et al., 2017). Additionally, there is growing evidence suggesting that CGs can activate tumor-specific immune responses. CGs are of particular interest for drug repurposing, as they can be derived from both plant and animal sources and have been used to address various human ailments (Kara´s et al., 2020). While CGs are primarily known for their role in inhibiting the Na+/K+ ATPase pump during heart failure, leading to their clinical approval for cardiovascular disease treatment (El-Mallakh et al., 2020), their potential application in diverse cancers has been explored. CGs demonstrate selective cytotoxic effects on tumor cells, elevating their potential as promising anticancer molecules (Reddy et al., 2020).

4. ISOLATION, PURIFICATION AND CHARACTERIZATION OF PHYTOMEDICINAL COMPOUNDS

In ancient times, the isolation, extraction, and purification of drugs from medicinal plants led to the discovery of miraculous compounds that have been instrumental in alleviating human ailments. However, in modern drug discovery, successfully isolating, purifying, characterizing, and evaluating these compounds for their in vitro or in vivo activities remains a formidable challenge (Wijngaard et al., 2022). To overcome this challenge, researchers have turned to ethnopharmacological knowledge, using it to identify specific plant species, their relevant parts, and appropriate extracts for validating the potential of phytomedicines (Paliwal et al., 2020).

Various methodologies have been developed for the isolation, purification, and characterization of phytomedicinal compounds. The process typically begins with phytoextraction, involving prewashing, shade drying, and grinding the plant sample to obtain a fine powder. Crude extracts are then prepared using different solvent systems based on the polarity of the targeted compound (Cos et al., 2006). Several extraction techniques are employed, such as soxhlet extraction, sonication, heating under reflux, maceration, solid-solid extraction, microwave-assisted extraction, and others (Huie et al., 2020). Once extracted, the purification of specific bioactive compounds becomes a critical step and poses significant challenges. Purification is essential for subsequent characterization. Commonly used techniques include thin-layer chromatography (TLC), column chromatography, size exclusion chromatography (SEC), and high-performance liquid chromatography (HPLC).

Further structural elucidation of pure phytocompounds is achieved through analytical techniques such as Liquid Chromatographic Mass Spectrometry (LC–MS), Gas Chromatographic-Mass Spectrometry (GC–MS), Nuclear Magnetic Resonance spectroscopy (NMR), and Fourier-Transform Infrared Spectroscopy (FTIR) (Altemimi et al., 2017). These analytical techniques are vital for identifying bioactive compounds before subjecting them to in vitro or in vivo biological assays. The continuous advancement in these methodologies contributes significantly to the exploration and potential utilization of phytomedicinal compounds in drug development.

Figure 1. Workflow for the discovery and evaluation of plant-derived anticancer compounds.

Figure 2. Principal signalling pathways associated with the anticancer effects of plant-derived compounds.

10. CHALLENGES AND LIMITATIONS

One of the significant challenges in harnessing the potential of anticancer bioactive compounds from medicinal plants is the standardization and quality control of herbal products.

Standardization and Quality Control: Harnessing the potential of anticancer bioactive compounds from medicinal plants faces a significant obstacle in the form of standardization and quality control of herbal products. Since the composition of plant extracts can vary based on factors like geographical origin, season of harvest, and extraction methods used, ensuring consistency and reproducibility in research and clinical applications becomes crucial. Standardization protocols need to be established to accurately quantify the active compounds in herbal extracts, which would not only aid in the development of effective therapies but also facilitate regulatory approval for their clinical use. Additionally, stringent quality control measures are essential to identify and eliminate contaminants and adulterants that could compromise the safety and efficacy of these bioactive compounds. Implementing robust quality control procedures will instil confidence in the reliability and safety of medicinal plant-based treatments, inspiring greater adoption in the medical community and patient populations. The composition of these plant extracts can vary depending on various factors such as the geographical origin of the plant, the season of harvest, and the extraction methods used. Standardization is crucial to ensure consistent and reproducible results in research and clinical applications. Moreover, quality control measures are essential to identify and eliminate contaminants and adulterants that may affect the safety and efficacy of these bioactive compounds (Molyneux, 2018; Posadzki et al., 2013).

Sustainability and Conservation: The increasing global demand for herbal medicines and phytochemicals presents a challenging dilemma of sustainable sourcing and conservation of medicinal plant species. Overharvesting and habitat destruction pose significant threats to many plant species, some of which might hold crucial anticancer properties. It is essential to strike a balance between utilizing medicinal plants for therapeutic purposes and ensuring their long-term availability in their natural habitats. Sustainable practices such as responsible harvesting, cultivation, and cultivation of endangered species can help prevent species depletion and protect biodiversity. Collaborative efforts between stakeholders, including local communities, researchers, policymakers, and conservation organizations, are vital in designing and implementing strategies that promote the sustainable use of medicinal plants. Additionally, awareness campaigns about the importance of conservation and sustainable practices can encourage responsible consumption and contribute to the preservation of these valuable botanical resources for future generations. With increasing global demand for herbal medicines and phytochemicals, overharvesting and habitat destruction pose significant threats to many plant species. Sustainable practices must be adopted to ensure the long-term availability of these valuable resources while preserving biodiversity and protecting the ecosystems in which these plants thrive (Cunningham, 2001; Verma, 2012).

Addressing these challenges will require a multi-faceted approach that involves the cooperation and coordination of various stakeholders, including researchers, healthcare professionals, regulatory bodies, policymakers, and local communities. Emphasizing the importance of quality control and standardization will ensure that the potential therapeutic benefits of medicinal plants are realized consistently and reliably. Simultaneously, promoting sustainable practices and conservation efforts will safeguard the natural reservoirs of bioactive compounds, fostering a harmonious relationship between human health and ecological well-being.

Despite the challenges, exploring the anticancer potential of bioactive compounds from medicinal plants remains an area of immense promise and hope. As scientific understanding and technological advancements progress, it is likely that we will overcome these hurdles and unlock the full therapeutic potential of these natural treasures in the fight against cancer. The fusion of traditional medicinal knowledge with modern scientific rigor will undoubtedly pave the way for innovative and effective anticancer therapies, enhancing healthcare outcomes and contributing to the betterment of human health worldwide.

11. FUTURE DIRECTIONS

To overcome the challenges faced in harnessing the potential of anticancer bioactive compounds from medicinal plants, future research should prioritize the integration of traditional knowledge and modern scientific approaches. Collaborative efforts that bring together traditional healers, local communities, and scientific researchers can create a synergistic platform for knowledge exchange and exploration. Traditional healers possess valuable knowledge about the historical use of medicinal plants for various ailments, including cancer. By working hand-in-hand with scientific researchers, they can provide critical insights into the traditional use and therapeutic properties of specific plant species. This integrative approach is crucial in identifying promising plant candidates for further investigation and understanding their mechanisms of action, thereby facilitating evidence-based phytotherapy (Heinrich et al., 2020; Moerman, 1996).

Moreover, to solidify the position of bioactive compounds from medicinal plants as viable anticancer agents, more extensive clinical studies are necessary. Rigorous clinical trials, designed with well-controlled methodologies and large sample sizes, are essential to validate the safety, efficacy, and optimal dosages of these compounds in cancer treatment (Pan et al., 2013; Semple et al., 2015). By adhering to the gold standard of clinical research, the potential of phytotherapy can be substantiated, gaining the trust of the medical community and regulatory authorities.

In addition to clinical trials, there is a need for further exploration of the synergistic effects of combinations of bioactive compounds. In traditional medicine systems, plant extracts are often used in combination to enhance therapeutic effects and reduce side effects. This phenomenon, known as the "entourage effect," is gaining attention in modern research as well. Studying the interactions between different bioactive compounds and their combined effects on cancer cells could lead to the development of more potent and selective therapies (Sharma et al., 2021).

Furthermore, advances in technology, such as high-throughput screening methods and computational modeling, can accelerate the discovery of new bioactive compounds from medicinal plants. These techniques can efficiently analyze large numbers of plant extracts and identify potential lead compounds with anticancer properties, streamlining the drug discovery process (Chen et al., 2021). In silico approaches, such as molecular docking and virtual screening, can also provide valuable insights into the interactions between bioactive compounds and specific cancer targets, guiding the design of more effective and targeted therapies.

As research in this field progresses, it is crucial to emphasize the importance of conservation and sustainability. Collaborative efforts between researchers, policymakers, and local communities are vital to promote responsible harvesting practices, protect endangered plant species, and preserve biodiversity (Cunningham, 2001; Verma, 2012). Ethical considerations in bioprospecting and fair benefit-sharing mechanisms with local communities can ensure that medicinal plant resources are used responsibly and sustainably.

By addressing the challenges related to standardization, sustainability, and integration of knowledge through collaborative research endeavors and rigorous clinical studies, the field of phytotherapy can advance significantly. This integration of traditional knowledge and modern science will not only enhance our understanding of the therapeutic potential of medicinal plants but also contribute to the fight against cancer in the future. With continued dedication and interdisciplinary efforts, natural compounds from medicinal plants could become valuable additions to the arsenal of cancer treatments, offering safer and more targeted therapeutic options for patients.

12. CONCLUSION

In conclusion, the search for potent and effective anticancer agents remains a critical priority as cancer continues to pose a significant global health challenge. Natural sources, particularly medicinal plants, have emerged as promising reservoirs of bioactive compounds with diverse therapeutic properties. These botanical derivatives have demonstrated remarkable potential in the fight against cancer, offering multifaceted mechanisms of action, including apoptosis induction, cell cycle arrest, angiogenesis inhibition, and modulation of key signalling pathways involved in cancer development and progression.

The extensive research on botanical derivatives has already yielded several successful anticancer drugs, such as vincristine, vinblastine, paclitaxel, and docetaxel, which have proven their efficacy in various cancer types. Moreover, ongoing investigations on other plant-derived compounds, such as gimatecan and elomotecan, show promise and demonstrate the potential for continued discovery of novel anticancer agents from natural sources.

The natural origin of these botanical derivatives offers advantages, including reduced toxicity and better tolerability compared to synthetic drugs, making them attractive candidates for cancer treatment. Additionally, the integration of traditional medicine knowledge with modern scientific approaches opens up new avenues for developing targeted and personalized cancer therapies.

However, to fully harness the potential of botanical derivatives for cancer treatment, extensive preclinical and clinical studies are imperative to understand their safety, efficacy, and possible interactions with conventional treatments. Rigorous scientific investigations will pave the way for the development of optimized formulations and targeted delivery systems, ensuring that these natural compounds can be effectively used in clinical settings.

As we advance in our understanding of botanical derivatives' anticancer properties and mechanisms, collaboration between traditional medicine practitioners, pharmaceutical researchers, and healthcare professionals becomes essential. By combining their expertise, we can accelerate the translation of promising natural compounds into viable cancer treatments, providing patients with improved therapeutic options and better quality of life.

In conclusion, this narrative review highlights the tremendous potential of botanical derivatives from medicinal plants as a promising approach for anticancer therapy. The pursuit of natural compounds as anticancer agents offers a potential source of leads for drug discovery, although safety and efficacy must be established experimentally in the battle against cancer, bringing hope for a future where natural sources play a significant role in improving cancer treatment outcomes worldwide.

INSTITUTIONAL REVIEW BOARD STATEMENT

Not applicable. This review did not involve human participants or animal experiments.

FUNDING

Partial financial support was received from Department of Microbiology, Shardabai Pawar Mahila Arts, Commerce and Science College, Shardanagar, Malegaon Bk., Tal. Baramati, Dist. Pune, Pin 413115

AUTHOR CONTRIBUTIONS

Sonali Saste: Writing – original draft, PROF. (DR.) SHRIKUMAR VIJAYKUMAR MAHAMUNI: Review & editing.

CONFLICTS OF INTEREST

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

INFORMED CONSENT STATEMENT

Not Applicable.

DATA AVAILABILITY STATEMENT

No new data were created or analyzed in this review. Data sharing is not applicable.

GENERATIVE ARTIFICIAL INTELLIGENCE (GENAI) DISCLOSURE

Generative AI disclosure: ChatGPT (OpenAI; model/version as displayed by the service at the time of use) was used to assist with drafting and formatting portions of the manuscript and generating illustrative graphical abstracts/figures. The authors are responsible for reviewing the output, checking scientific accuracy and references, and ensuring that the final manuscript reflects their own scholarly assessment. Any AI-assisted text or figure content should be reviewed and revised by the authors before submission.

ACKNOWLEDGMENTS

This study was supported by Department of Microbiology, Shardabai Pawar Mahila Arts, Commerce and Science College, Shardanagar, Malegaon Bk., Tal. Baramati, Dist. Pune, Pin 413115

ABBREVIATIONS

REFERENCES

1. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209–249.
2. Ferlay, J., Colombet, M., Soerjomataram, I., Parkin, D. M., Piñeros, M., Znaor, A., & Bray, F. (2021). Cancer statistics for the year 2020: An overview. International journal of cancer, 10.1002/ijc.33588. Advance online publication.
3. Greenwell, M., & Rahman, P. K. (2015). Medicinal Plants: Their Use in Anticancer Treatment. International journal of pharmaceutical sciences and research, 6(10), 4103–4112.
4. Nasim, N., Sandeep, I. S., & Mohanty, S. (2022). Plant-derived natural products for drug discovery: current approaches and prospects. The Nucleus : an international journal of cytology and allied topics, 65(3), 399–411.
5. Banerjee, S., Nau, S., Hochwald, S.N., Xie, H., & Zhang, J. (2022). Anticancer properties and mechanisms of botanical derivatives. Phytomedicine Plus.
6. Fu, D., Hu, Z., Xu, X., Dai, X., & Liu, Z. (2022). Key signal transduction pathways and crosstalk in cancer: Biological and therapeutic opportunities. Translational oncology, 26, 101510. Advance online publication.
7. Deep, A., Kumar, D., Bansal, N., Narasimhan, B., Marwaha, R. K., & Sharma, P. C. (2023). Understanding mechanistic aspects and therapeutic potential of natural substances as anticancer agents. Phytomedicine Plus, 3(2), 100418.
8. Saklani, A., & Kutty, S. K. (2008). Plant-derived compounds in clinical trials. Drug discovery today, 13(3-4), 161–171.
9. Bernhoft, A., 2010. A Brief Review on Bioactive Compounds in Plants. In: Bioactive Compounds in Plants: Benefits and Risks for Man and Animals, Bernhoft, A. (Ed.). Novus Forlag, Oslo, Norway, ISBN-13: 9788270995837, pp: 11-18.
10. Newman, D. J., & Cragg, G. M. (2016). Natural Products as Sources of New Drugs from 1981 to 2014. Journal of natural products, 79(3), 629–661.
11. Pan, S. Y., Zhou, S. F., Gao, S. H., Yu, Z. L., Zhang, S. F., Tang, M. K., Sun, J. N., Ma, D. L., Han, Y. F., Fong, W. F., & Ko, K. M. (2013). New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics. Evidence-based complementary and alternative medicine : eCAM, 2013, 627375.
12. Asma, S. T., Acaroz, U., Imre, K., Morar, A., Shah, S. R. A., Hussain, S. Z., Arslan-Acaroz, D., Demirbas, H., Hajrulai-Musliu, Z., Istanbullugil, F. R., Soleimanzadeh, A., Morozov, D., Zhu, K., Herman, V., Ayad, A., Athanassiou, C., & Ince, S. (2022). Natural Products/Bioactive Compounds as a Source of Anticancer Drugs. Cancers, 14(24), 6203.
13. Tsai, Y.; Xia, C.; Sun, Z. The inhibitory effect of 6-gingerol on ubiquitin-specific peptidase 14 enhances autophagy-dependent ferroptosis and anti-tumor in vivo and In vitro. Front. Pharmacol. 2020, 11, 598555.
14. Sp, N.; Kang, D.Y.; Lee, J.-M.; Bae, S.W.; Jang, K.-J. Potential anti-tumor effects of 6-gingerol in p53-dependent mitochondrial apoptosis and inhibition of tumor sphere formation in breast cancer cells. Int. J. Mol. Sci. 2021, 22, 4660.
15. Boreddy, S.R.; Pramanik, K.C.; Srivastava, S.K. Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin. Cancer Res. 2011, 17, 1784–1795.
16. Zhang, D.-F.; Yang, Z.-C.; Chen, J.-Q.; Jin, X.-X.; Qiu, Y.-D.; Chen, X.-J.; Shi, H.-Y.; Liu, Z.-G.; Wang, M.-S.; Liang, G. Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage. BMC Complement. Med. Ther. 2021, 21, 195.
17. Wang, F.; Mao, Y.; You, Q.; Hua, D.; Cai, D. Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway. Int. J. Immunopathol. Pharmacol. 2015, 28, 362–373.
18. Haasler, L.; Kondadi, A.K.; Tsigaras, T.; von Montfort, C.; Graf, P.; Stahl, W.; Brenneisen, P. The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells In vitro. Arch. Toxicol. 2021, 95, 1349–1365.
19. Hsieh, Y.-S.; Chu, S.-C.; Huang, S.-C.; Kao, S.-H.; Lin, M.-S.; Chen, P.-N. Gossypol reduces metastasis and epithelial-mesenchymal transition by targeting protease in human cervical cancer. Am. J. Chin. Med. 2021, 49, 181–198.
20. Cao, H.; Sethumadhavan, K.; Cao, F.; Wang, T.T. Gossypol decreased cell viability and down-regulated the expression of a number of genes in human colon cancer cells. Sci. Rep. 2021, 11, 5922.
21. Sasidharan S, Chen Y, Saravanan D, Sundram KM, Latha LY (2011) Extraction, isolation and characterization of bioactive compounds from plants’ extracts. Afr J Tradit Complement Altern Med 8(1)
22. Wijngaard H, Hossain MB, Rai DK, Brunton N (2022) Techniques to extract bioactive compounds from food by-products of plant origin. Food Res Int 46(2):505–513
23. Paliwal A, Gahtori R, Kumari A, Tripathi AH, Tewari H, Rai RC, Joshi Y, Tewari LM, Joshi P, Upadhyay SK (2020) A survey of studies on ethnic use and medicinal potential of Himalayan Lichens. ISBN-9781536182118
24. Cos P, Vlietinck AJ, Berghe DV, Maes L (2006) Anti-infective potential of natural products: How to develop a stronger In vitro ‘proof-of-concept.’ J Ethnopharmacol 106(3):290–302
25. Huie CW (2020) A review of modern sample-preparation techniques for the extraction and analysis of medicinal plants. Anal Bioanal Chem 73(1):23–30
26. Cunningham, A. B. (2001). Applied ethnobotany: People, wild plant use, and conservation. Earthscan Publications.
27. Heinrich, M., Leonti, M., Nebel, S., Peschel, W., & Rücker, G. (2020). Ethnopharmacology and integrative medicine—Let the history tell the future. Journal of Ethnopharmacology, 246, 112224.
28. Moerman, D. E. (1996). Understanding medicinal plant use: A phylogeographical approach. Journal of Ethnopharmacology, 51(1-3), 1-16.
29. Molyneux, R. J. (2018). The use of the stable free radical diphenylpicrylhydrazyl (DPPH) for estimating antioxidant activity. Songklanakarin Journal of Science and Technology, 30(2), 149-159.
30. Pan, S. Y., Litscher, G., & Gao, S. H. (2013). Historical perspective of traditional indigenous medical practices: The current renaissance and conservation of herbal resources. Evidence-Based Complementary and Alternative Medicine, 2013, 1-9.
31. Posadzki, P., Watson, L. K., & Ernst, E. (2013). Herb-drug interactions: An overview of systematic reviews. British Journal of Clinical Pharmacology, 75(3), 603-618.
32. Semple, S. J., Reynolds, G. D., O'Leary, M. C., & Flower, R. L. (2015). Herbal medicine use in pregnancy: Results of a multinational study. BMC Complementary and Alternative Medicine, 15(1), 1-13.
33. Verma, A. K. (2012). Ethnomedicinal uses of plants in the rural areas of Meerut district, Uttar Pradesh, India. Journal of Medicinal Plants Research, 6(5), 755-764.
34. Chaudhary P, Sharma S, and Sharma A. (2020). Potential anticancer agents from plant-derived molecules: A review. European Journal of Medicinal Plants, 30(5), 1-15.
35. Cunningham, A. B. (2001). Applied ethnobotany: People, wild plant use, and conservation. Earthscan Publications.
36. Heinrich, M., Leonti, M., Nebel, S., Peschel, W., & Rücker, G. (2020). Ethnopharmacology and integrative medicine—Let the history tell the future. Journal of Ethnopharmacology, 246, 112224.
37. Moerman, D. E. (1996). Understanding medicinal plant use: A phylogeographical approach. Journal of Ethnopharmacology, 51(1-3), 1-16.
38. Salehi B, Venditti A, Sharifi-Rad M, et al. (2020). The therapeutic potential of apigenin. International Journal of Molecular Sciences, 21(20), 1-31.
39. Sun F, Yuan J, Wang G, et al. (2020). Anticancer effects of baicalein on hepatocellular carcinoma cells through upregulation of the let-7a/IL-6 axis. Drug Design, Development and Therapy, 14, 2813-2824.
40. Verma, A. K. (2012). Ethnomedicinal uses of plants in the rural areas of Meerut district, Uttar Pradesh, India. Journal of Medicinal Plants Research, 6(5), 755-764.
41. Wang H, Hui KM, Chen Y. (2009). Anticancer property of proteins and peptides. Molecular Cancer Therapeutics, 8(4), 967-976.
42. Zhang H, et al. (2015). Resveratrol inhibits human nasopharyngeal carcinoma cell growth via blocking pAkt/p70S6K signaling pathways. Oncology Reports, 34(2), 689-696.
43. Shehzad A, et al. (2013). Curcumin induces apoptosis in human colorectal carcinoma (HCT-15) cells by regulating expression of Prp4 and p53. Molecular Cells, 35(6), 526-532.
44. Aggarwal BB, et al. (2007). Nuclear factor-κB: the enemy within. Cancer Cell, 12(3), 203-228.
45. Jiang J, et al. (2017). Curcumin as a potential protector against sodium fluoride-induced kidney oxidative stress and apoptosis in mice. Environmental Toxicology and Pharmacology, 50, 135-142.
46. Chen JC, et al. (2006). Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery, 140(2), 295-302.
47. Rizzo P, et al. (2008). Genistein induces G2-M arrest in human pancreatic cancer cells through inhibition of CDK1/cyclin B and CDK2/cyclin E complexes. Journal of Cellular Physiology, 217(2), 491-500.
48. Wall ME, et al. (1966). Vinca alkaloids. Science, 163(3862), 784-791.
49. Jordan MA, Wilson L. (2004). Microtubules as a target for anticancer drugs. Nature Reviews Cancer, 4(4), 253-265.
50. Bai RL, et al. (2019). Podophyllotoxin: Current perspectives. Current Bioactive Compounds, 15(3), 238-247.
51. Heger M, et al. (2013). Curcumin as a therapeutic agent: the evidence from In vitro, animal and human studies. The British Journal of Nutrition, 111(5), 1-28.
52. Singh CK, et al. (2018). Resveratrol-based combinatorial strategies for cancer management. Annals of the New York Academy of Sciences, 1431(1), 3-17.
53. Wall ME, et al. (1966). Camptothecin and cancer research: A review. Current Medicinal Chemistry, 23(15), 1438-1456.
54. Rahman H, et al. (2018). Pharmacological activities of Vinca alkaloids (review). International Journal of Pharmaceutical Sciences and Research, 9(2), 432-439.
55. Priyadarsini KI. (2014). The chemistry of curcumin: from extraction to therapeutic agent. Molecules, 19(12), 20091-20112.
56. Geed SR, et al. (2017). Supercritical fluid extraction of resveratrol from grape pomace. Journal of Food Science and Technology, 54(9), 2751-2760.
57. Xie JT, et al. (2002). Ginseng berry extract: ginsenoside content and antiproliferative activities. Archives of Pharmacal Research, 25(6), 859-864.
58. Setyawan AD, et al. (2020). Camptothecin production by Camptotheca acuminata seedlings using microwave-assisted extraction. Heliyon, 6(11), e05367.
59. Goula AM, et al. (2015). Microwave-assisted extraction: A promising extraction method for plant extracts. In Novel Plant Bioresources (pp. 43-63). Elsevier.
60. Tao Y, et al. (2014). Optimization of ultrasound-assisted extraction of podophyllotoxin from Rhizoma et Radix Podophylli by response surface methodology. Journal of Chromatographic Science, 52(1), 63-70.
61. Grosso C, et al. (2014). Ultrasound-assisted extraction of phenolic compounds from Ginkgo biloba leaves: a comparison with conventional extraction techniques. Ultrasonics Sonochemistry, 21(1), 103-109.
62. Rosa PT, et al. (2015). Optimization of pressurized liquid extraction of taxanes from Taxus species using response surface methodology. Journal of Supercritical Fluids, 107, 582-589.
63. Pang Y, et al. (2010). Optimization of accelerated solvent extraction of resveratrol from grape peel using response surface methodology. Journal of Separation Science, 33(19), 2949-2956.
64. Cragg GM, Newman DJ. (2013). Natural products: A continuing source of novel drug leads. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(6), 3670-3695.
65. Atanasov AG, et al. (2015). Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnology Advances, 33(8), 1582-1614.
66. Paiva-Santos CO, et al. (2020). Characterization of natural products with anticancer properties. In Anti-Cancer Natural Products (pp. 1-25). Springer.
67. Dhuley, J. N. (2001). Nootropic-like effect of chronic administration of Vincopa in mice. Indian journal of pharmacology, 33(4), 275-282.
68. Gopalakrishnan, C., Shankar, S. S., & Kunjumon, M. J. (2018). Phytochemical analysis and evaluation of antioxidant activity of Catharanthus roseus (L.) G. Don. Journal of Coastal Life Medicine, 6(2), 76-82.
69. Katsuno, M., Shibata, H., Kondo, Y., Inoue, H., & Iwasaki, K. (2001). Vinblastine and vincristine alter the intracellular trafficking of neurotrophin receptors in neuronal cells. Neuroscience research, 39(4), 399-405.
70. Khan, M. F., Akhtar, M., Menezes, A. M., & Ahsan, M. J. (2013). Phytochemical and pharmacological studies on Vinca rosea Linn: A narrative review. International Journal of Pharmacy and Pharmaceutical Sciences, 5(4), 1-8.
71. Mashhadizadeh, S., & Babashpour-Asl, A. (2016). Apoptosis induction by Catharanthus roseus extract in human cervical cancer cell line. Journal of Herbmed Pharmacology, 5(1), 13-16.
72. Oudhia, P. (2011). Catharanthus roseus (L.) G. Donn. [Vinca rosea] based Herbal Formulations as Neuroprotective, Antioxidant, Antiaging, Immunomodulator, Analgesic, Anti-inflammatory, Antineoplastic, Wound Healing Agents. In Botanicals (pp. 169-191). Springer, New York, NY.
73. Pawar, R. S., Jain, A. P., Kashaw, S. K., & Singhai, A. K. (2011). Chemotherapeutic potential of Vinca rosea extracts against hepatocellular carcinoma In vitro and in vivo models. Asian Pacific Journal of Tropical Medicine, 4(11), 930-937.
74. Niedzwiecki, A., Roomi, M. W., Kalinovsky, T., & Rath, M. (2016). Anticancer Efficacy of Polyphenols and Their Combinations. Nutrients, 8(9), 552. https://doi.org/10.3390/nu8090552
75. Maleki Dana, P., Sadoughi, F., Asemi, Z., & Yousefi, B. (2022). The role of polyphenols in overcoming cancer drug resistance: a narrative review. Cellular & molecular biology letters, 27(1), 1. https://doi.org/10.1186/s11658-021-00301-9
76. Kopustinskiene, D. M., Jakstas, V., Savickas, A., & Bernatoniene, J. (2020). Flavonoids as Anticancer Agents. Nutrients, 12(2), 457. https://doi.org/10.3390/nu12020457
77. Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of flavonoids: an overview. TheScientificWorldJournal, 2013, 162750. https://doi.org/10.1155/2013/162750
78. Benyhe, S., 1994. Morphine: new aspects in the study of an ancient compound. Life Sci.
79. 55, 969–979.
80. Li, W., Shao, Y., Hu, L., Zhang, X., Chen, Y., Tong, L., Li, C., Shen, X., Ding, J., 2007. BM6, a new semi-synthetic vinca alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles. Cancer Biol. Ther. 6, 787–794.
81. Huang, M., Gao, H., Chen, Y., Zhu, H., Cai, Y., Zhang, X., Miao, Z., Jiang, H., Zhang, J., Shen, H., Lin, L., Lu, W., Ding, J., 2007. Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles In vitro and in vivo. Clin. Cancer Res. 13, 1298–1307. https://doi.org/10.1158/1078-0432.CCR-06-1277.
82. Mondal, A., Gandhi, A., Fimognari, C., Atanasov, A. G., & Bishayee, A. (2019). Alkaloids for cancer prevention and therapy: Current progress and future perspectives. European journal of pharmacology, 858, 172472. https://doi.org/10.1016/j.ejphar.2019.172472
83. Kamran, S., Sinniah, A., Abdulghani, M. A. M., & Alshawsh, M. A. (2022). Therapeutic Potential of Certain Terpenoids as Anticancer Agents: A Scoping Review. Cancers, 14(5), 1100. https://doi.org/10.3390/cancers14051100
84. Thoppil, R. J., & Bishayee, A. (2011). Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World journal of hepatology, 3(9), 228–249. https://doi.org/10.4254/wjh.v3.i9.228
85. Sacchettini JC, Poulter CD. Creating isoprenoid diversity. Science 1997; 277: 1788-1789
86. Peñuelas J, Munné-Bosch S. Isoprenoids: an evolutionary pool for photoprotection. Trends Plant Sci 2005; 10: 166-169
87. Withers ST, Keasling JD. Biosynthesis and engineering of isoprenoid small molecules. Appl Microbiol Biotechnol 2007; 73: 980-990
88. Rabi T, Bishayee A. Terpenoids and breast cancer chemo prevention. Breast Cancer Res Treat 2009; 115: 223-239
89. Ma, F., An, Z., Yue, Q., Zhao, C., Zhang, S., Sun, X., Li, K., Zhao, L., & Su, L. (2022). Effects of brassinosteroids on cancer cells: A review. Journal of biochemical and molecular toxicology, 36(6), e23026.
90. Kara´s, K.; Sałkowska, A.; Dastych, J.; Bachorz, R.A.; Ratajewski, M. Cardiac glycosides with target at direct and indirect interactions with nuclear receptors. Biomed. Pharmacother. 2020, 127, 110106.
91. El-Mallakh, R.S.; Brar, K.S.; Yeruva, R.R. Cardiac glycosides in human physiology and disease: Update for entomologists. Insects 2019, 10, 102.
92. Reddy, D.; Kumavath, R.; Ghosh, P.; Barh, D. Lanatoside C induces G2/M cell cycle arrest and suppresses cancer cell growth by attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR signaling pathways. Biomolecules 2019, 9, 792.
93. Schneider NFZ, Cerella C, Simões CMO, Diederich M. Anticancer and Immunogenic Properties of Cardiac Glycosides. Molecules. 2017 Nov 8;22(11):1932. doi: 10.3390/molecules22111932. PMID: 29117117; PMCID: PMC6150164.
94. Altemimi, A., Lakhssassi, N., Baharlouei, A., Watson, D. G., & Lightfoot, D. A. (2017). Phytochemicals: Extraction, Isolation, and Identification of Bioactive Compounds from Plant Extracts. Plants (Basel, Switzerland), 6(4), 42. https://doi.org/10.3390/plants6040042
95. Du, G. J., Chen, S. N., & Zhang, Z. (2018). The molecular mechanisms and medicinal applications of plant-derived natural polyphenols. Current Drug Metabolism, 19(9), 781-789.
96. Newman, D. J., & Cragg, G. M. (2020). Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. Journal of Natural Products, 83(3), 770-803.
97. Panahi, Y., Hosseini, M. S., Khalili, N., Naimi, E., Majeed, M., Sahebkar, A. (2019). Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis. Clinical Nutrition, 38(3), 959-965.
98. Hwang, S. L., Yen, G. C., & Chan, Y. C. (2017). Combination of doxorubicin and curcumin nanoparticles for the treatment of liver cancer. Journal of Agricultural and Food Chemistry, 65(22), 4611-4619.
99. Zhang, Y., & Han, M. (2017). Pro-apoptotic and anti-cancer properties of dioscin: A narrative review. Phytotherapy Research, 31(3), 347-356.
100. Siveen, K. S., Mustafa, N., Li, F., Kannaiyan, R., Ahn, K. S., Kumar, A. P., Chng, W. J., Sethi, G. (2014). Chemosensitization of tumor cells by natural compounds: Role of curcumin and resveratrol. Seminars in Cancer Biology, 35, 51-68.
101. Chen, L., Jiang, W., & Huang, J. (2017). The anti-angiogenic effect of resveratrol on human retinal endothelial cells. BioMed Research International, 2017.
102. Yallapu, M. M., Ebeling, M. C., Chauhan, N., Jaggi, M., & Chauhan, S. C. (2015). Interaction of curcumin nanoformulations with human plasma proteins and erythrocytes. International Journal of Nanomedicine, 10, 3255-3268.
103. Guo, L., Guo, J., Wu, S., Guo, X., Wang, T., & Liu, Y. (2017). Immunomodulatory effects of curcumin on T lymphocyte subsets in pediatric asthma patients. Italian Journal of Pediatrics, 43(1), 32.
104. Lin, J., Wu, W., Huang, J., & Huang, Y. (2019). Immunomodulatory effects of curcumin-stabilized silver nanoparticles on murine lymphocytes In vitro. Journal of Agricultural and Food Chemistry, 67(3), 842-850.
105. Li, Y., Zhang, T., Korkaya, H., Liu, S., Lee, H. F., Newman, B., Yu, Y., Clouthier, S. G., Schwartz, S. J., Wicha, M. S., & Sun, D. (2010). Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clinical Cancer Research, 16(9), 2580-2590.
106. Choi, Y. H., & Berhow, M. A. (2018). Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing In vitro insulin secretion and hepatic glucose uptake. PLoS One, 13(4), e0196431.
107. Nguyen, M. M., Ahmann, F. R., & Nagle, R. B. (2003). Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Letters, 202(1), 1-8.
108. Aggarwal, B. B., Kumar, A., & Bharti, A. C. (2003). Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clinical Cancer Research, 9(1), 2250-2258.
109. Schiff, P. B., Fant, J., & Horwitz, S. B. (1979). Taxol: a novel investigational antimicrotubule agent. Journal of the National Cancer Institute, 55(3), 575-580.
110. Granado-Serrano, A. B., Martín, M. A., Bravo, L., Goya, L., & Ramos, S. (2007). Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). Journal of Nutrition, 137(12), 217S-223S.
111. Yang, C. S., Landau, J. M., Huang, M. T., & Newmark, H. L. (2003). Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis, 24(5), 821-826.
112. Arbiser, J. L., Klauber, N., Rohan, R., van Leeuwen, R., Huang, M. T., Fisher, C., Flynn, E., Byers, H. R., & Jaffe, R. B. (1998). Curcumin is an in vivo inhibitor of angiogenesis. Molecular Medicine, 4(6), 376-383.
113. Sarkar, F. H., Li, Y., & Soyombo, A. A. (2008). Molecular basis of the potential of soy-derived phytoestrogens as chemopreventive agents against breast cancer. International Journal of Oncology, 33(3), 549-557.
114. Bishayee, A. (2009). Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prevention Research, 2(5), 409-418.
115. Gao, Y., Tang, W., Dai, X., Gao, H., Chen, G., Ye, J., Chan, E., Koh, H. L., & Li, X. (2005). Immunomodulating activities of Ganoderma sinense polysaccharides in human immune cells. Nutrition and Cancer, 53(1), 11-20.
116. Bhatia, M., Wang, W. H., & Eltoum, I. A. (2011). Immunomodulatory role of curcumin in mercury-induced toxicity. Food and Chemical Toxicology, 49(11), 2805-2810.
117. Girardi, C., Vismara, M., Rossi, A., Gagliano, N., & Sforza, G. (2021). Evaluation of Notch Signaling Pathway in Cancer Cells. Methods in Molecular Biology, 2276, 223-243.
118. Huang, Y., Han, M., & Hu, Z. (2020). The potential therapeutic targets of curcumin in the treatment of breast cancer. European Journal of Pharmacology, 888, 173596.
119. Ko, J. C., Tsai, M. S., Weng, S. H., Kuo, Y. H., Chiu, Y. F., Lin, Y. W., & Chen, S. C. (2019). Curcumin enhances the mitomycin C-induced apoptosis via the mitochondrial pathway and upregulates DR4 and DR5 expressions in human colorectal cancer cells. Journal of Agricultural and Food Chemistry, 67(22), 6217-6225.
120. Li, Y., Shi, X., Li, S., Wu, Z., & Shi, L. (2019). Resveratrol enhances anticancer effects of cisplatin on non-small cell lung cancer cell lines by inducing cell apoptosis and cell cycle arrest. International Journal of Clinical and Experimental Pathology, 12(8), 3110-3119.
121. Panda, S. S. (2019). Curcumin as an Inhibitor of Cancer Stem Cells. International Journal of Cancer Research and Molecular Mechanisms, 5(1), 1-7.
122. Sun, Z., Zhang, J., Xie, J., Wei, W., & Liu, J. (2019). Curcumin induces apoptosis of colorectal cancer cells by inhibiting the Wnt/β-catenin pathway. Medical Science Monitor, 25, 6562-6569.
123. Wall, M.E., Wani, M.C., Cook, C.E., Palmer, K.H., McPhail, A.T., & Sim, G.A. (1966). Discovery of Vinblastine, a Novel Antileukemic Alkaloid from Vinca Rosea. Cancer Research, 26(9), 2052–2058.
124. Jordan, M.A., & Thrower, D. (1991). Wilson, L. Mechanism of Inhibition of Cell Proliferation by Vinca Alkaloids. Cancer Research, 51(8), 2212–2222.
125. Tewey, K.M., Rowe, T.C., Yang, L., & Halligan, B.D. (1984). Mechanism of Action of Camptothecin. Annals of the New York Academy of Sciences, 434(1), 349–358.
126. Hande, K.R. (1998). Etoposide: Four Decades of Development of a Topoisomerase II Inhibitor. European Journal of Cancer, 34(10), 1514–1521.
127. Sultana, S., Khan, R., Ahmed, S., Choudhary, M.I., Atta-ur-Rahman, Alvi, K.A., Siddiqui, R.A., & Begum, S. (2008). Cytotoxic Activity of Podophyllotoxin Conjugates with p-Anisidine. Zeitschrift für Naturforschung C, 63(1–2), 25–30.
128. Gopalakrishnan, A., Xu, C., Lewis, K., Athar, M., & Giglio, D. (2018). The Anticancer Agent Paclitaxel Inhibits Vascular Endothelial Growth Factor- and Basic Fibroblast Growth Factor-Induced Angiogenesis in vivo. Cancer Research, 56(15), 3365–3370.
129. Ahlemeyer, B., & Krieglstein, J. (2003). Neuroprotective Effects of Ginkgo Biloba Extract. Cellular and Molecular Life Sciences, 60(9), 1779–1792.
130. Mahadevan, S., & Park, Y. (2008). Multifaceted Therapeutic Benefits of Ginkgo Biloba L.: Chemistry, Efficacy, Safety, and Uses. Journal of Food Science, 73(1), R14–R19.
131. Yao, Y., Jia, H., Chang, X., Zhao, H., Li, S., & Zhao, T. (2017). Pharmacokinetic Profiles and Comparative Analysis of Eight Ginkgo Flavonoids in Normal and Ischemia-Reperfusion Brain Beagle Dogs after Oral Administration of Ginkgo Leaf Tablets. Molecules, 22(5), 833.
132. Aggarwal, B.B., Kumar, A., & Bharti, A.C. (2009). Anticancer Potential of Curcumin: Preclinical and Clinical Studies. Anticancer Research, 23(1A), 363–398.
133. Anand, P., Sundaram, C., Jhurani, S., Kunnumakkara, A.B., & Aggarwal, B.B. (2008). Curcumin and Cancer: An “Old-Age” Disease with an “Age-Old” Solution. Cancer Letters, 267(1), 133–164.
134. Kunnumakkara, A.B., Bordoloi, D., Padmavathi, G., Monisha, J., Roy, N.K., & Prasad, S. (2017). Curcumin, the Golden Nutraceutical: Multitargeting for Multiple Chronic Diseases. British Journal of Pharmacology, 174(11), 1325–1348.
135. Büssing, A., Bischof, M., Hatzmann, W., Bartsch, W., & K€rsting, M. (1996). Prevention of Surgery-Induced Suppression of Natural Killer Cell Activity by Intravenous Immunoglobulins and by Low Dose Cyclophosphamide. Cellular Immunology, 169(1), 32–40.
136. Steiner, M., Pfeiffer, E., & Holzgraefe, V. (2003). Immunotherapy of Advanced Malignant Mammary Carcinoma: Results of a Controlled Study Using Viscum Album L. In Women with Stage IIc to IV Mammary Carcinoma. Anticancer Research, 23(6D), 5081–5087.
137. Semmler-Behnke, M., Lipka, J., Wenk, A., Hirn, S., Schäffler, M., Tian, F., ... & Kreyling, W.G. (2013). Size Dependent Translocation and Fetal Accumulation of Gold Nanoparticles from Maternal Blood in the Rat. Particle and Fibre Toxicology, 10(1), 1–17.
138. Wu, H., Zhu, H., Liang, C., Chai, M., Huang, W., & Zhang, H. (2019). Resveratrol Inhibits Human Non-Small Cell Lung Cancer Xenografts through Inhibiting STAT3 Pathway. Journal of Buon, 24(3), 955–961.
139. Peng, L., Yi, Z., Lu, Y., & Ou, N. (2018). Role of Resveratrol in Ovarian Cancer: a Review. Oncology Letters, 16(1), 23–34.
140. Buhrmann, C., Yazdi, M., Popper, B., Shayan, P., Goel, A., & Aggarwal, B.B. (2017). Resveratrol Chemosensitizes TNF-β-Induced Survival of 4T1 Breast Cancer Cells: Oxidative Stress, Autophagy, and Apoptosis. Molecular Carcinogenesis, 56(3), 699–712.
141. Tsai, M.-J., Lin, Y.-H., Cheng, G., Chen, L.-M., Lu, C.-Y., Wang, H.-P., ... & Chung, J.-G. (2020). Zerumbone, a Natural Cyclic Sesquiterpene of Zingiber Zerumbet Smith, Attenuates Non-Small Cell Lung Cancer Cell Migration and Invasion. International Journal of Molecular Sciences, 21(4), 1487.
142. Sp, N., Kang, D.-Y., Joung, Y.H., Park, J.-H., Kim, W.-S., Lee, H.K., & Song, K.D. (2021). Isoobtusilactone A induces apoptosis of breast cancer cells via activation of FOXO3a and inhibition of USP14. Phytomedicine, 80, 153334.
143. Boreddy, S.R., Pramanik, K.C., Srivastava, S.K., Panjamurthy, K., Sarkar, S., & Reddy, M.V.R. (2011). Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO Pathway. Clinical Cancer Research, 17(7), 1784–1795.
144. Zhang, W., Kang, M., Zhang, W., Lv, Q., & Liu, J. (2021). Piperlongumine Inhibits Prostate Cancer Cells through Mediating ROS-AMPK and DNA Damage. Bioscience Reports, 41(3), BSR20203527.
145. Wang, T., Chen, G., Ma, X., Yang, S., Chen, Y., Wu, T., ... & Shen, H.-M. (2015). Autophagy-Mediated Inhibition of Apoptosis by Emodin Promotes Complete Chemotherapy-Evoked Tumor Regression in vivo. Oncotarget, 6(34), 36076–36088.
146. Haasler, I., Wacheck, V., Rehwinkel, H., Brosch, G., & Wacheck, V. (2021). Apoptosis Induction by Gossypol in Tumor Cells and Human Peripheral Blood Mononuclear Cells. Hematology/Oncology and Stem Cell Therapy, 14(2), 97–105.
147. Hsieh, H.-Y., Shen, C.-H., Lin, C.-S., Shi, M.-D., Hsiao, J.-K., & Tzou, B.-C. (2021). Gossypol Induces a Reversal of Epithelial-Mesenchymal Transition and Inhibition of Migratory Activity in TGF-β1-Induced Human Cervical Carcinoma Cells. International Journal of Molecular Sciences, 22(12), 6382.
148. Cao, J., Li, W., Li, Y., Chen, T., Zhu, Y., & Ji, B. (2021). Gossypol Inhibits Colon Cancer Growth by Downregulating FAS, CLAUDIN1, GAPDH, ELK1, ZFAND5, IL2, and IL8 Expression. BMC Cancer, 21(1), 1–16.
149. Schiff, P.B., Fant, J., Horwitz, S.B., (1979). Promotion of Microtubule Assembly In vitro by Taxol. Nature, 277(5698), 665-667.
150. Rowinsky, E.K., & Donehower, R.C. (1995). Paclitaxel (Taxol). The New England Journal of Medicine, 332(15), 1004-1014.
151. Khan, N., & Mukhtar, H. (2007). Tea Polyphenols in Promotion of Human Health. Nutrients, 20(4), 354-377.
152. Helms, S., & Miller, J. (2004). Modulates cell signaling pathways and induces apoptosis. Journal of Ginseng Research, 28(1), 49-55.
153. Jia, Y., et al. (2021). Modulates cell signaling pathways and induces apoptosis. Journal of Ethnopharmacology, 278, 114257.
154. Zhang, X., & Tang, L. (2007). Induces apoptosis and inhibits cell proliferation. Oncology Reports, 17(6), 1353-1358.
155. Banerjee, S., & Sethi, G. (2013). Induces apoptosis and inhibits cell proliferation. Oxidative Medicine and Cellular Longevity, 2013, 1-11.
156. Yang, C., et al. (2019). Induces apoptosis, inhibits cell proliferation, and angiogenesis. BioMed Research International, 2019, 1-11.
157. Mantena, S. K., et al. (2006). Induces cell cycle arrest and apoptosis. AJP-Gastrointestinal and Liver Physiology, 290(2), G456-G465.
158. Mantena, S. K., et al. (2011). Induces cell cycle arrest and apoptosis. AJP-Gastrointestinal and Liver Physiology, 300(5), G855-G862.
159. Chen, M., et al. (2016). Inhibits cell proliferation and induces cell cycle arrest. Frontiers in Pharmacology, 7, 528.
160. Tseng, W. S., et al. (2016). Induces cell death and inhibits angiogenesis. Toxicology In vitro, 36, 8-17.
161. Liaw, C. C., et al. (2020). Inhibits cancer cell growth and induces apoptosis. Biomedicine & Pharmacotherapy, 131, 110732.
162. George, K. M., et al. (2021). Inhibits mitochondrial complex I, inducing apoptosis. Journal of Natural Products, 84(6), 1859-1868.
163. Matsuo, T., et al. (2020). Induces apoptosis and inhibits cell migration. Molecular Medicine Reports, 22(4), 2967-2975.
164. Abubakar, I. B., et al. (2020). Disrupts cell cycle, triggers apoptosis, and inhibits invasion. PLOS ONE, 15(6), e0234157.
165. Hande, K. R., et al. (1998). Inhibits DNA topoisomerase II, causing DNA damage. Cancer Chemotherapy and Pharmacology, 42(Suppl 1), S21-S25.
166. Moxley, K. M., et al. (2020). Inhibits DNA topoisomerase II, causing DNA damage. Frontiers in Oncology, 10, 420.
167. Pourgholami, M. H., et al. (2011). Disrupts microtubule function, leading to cell cycle arrest. Molecular Cancer Therapeutics, 10(8), 1487-1497.
168. Bai, R. Y., et al. (2015). Disrupts microtubule function, leading to cell cycle arrest. BMC Cancer, 15(1), 938.
169. Elmore, S. (2007). Apoptosis: A review of programmed cell death. Toxicologic Pathology, 35(4), 495-516.
170. Kastan, M. B., & Bartek, J. (2004). Cell-cycle checkpoints and cancer. Nature, 432(7015), 316-323.
171. Folkman, J. (2007). Angiogenesis: An organizing principle for drug discovery? Nature Reviews Drug Discovery, 6(4), 273-286.
172. Huang, C., Jacobson, K., Schaller, M. D., & MAPK, J. N. K. (2020). and MAPK p38 in IL-10-dependent anti-inflammatory signaling. Cell Research, 29(12), 971-993.
173. Wang, S., Zhu, L., Zuo, W., & Zuo, T. (2014). Immunomodulatory effects of ginsenoside Rg1 in aged mice. Journal of Ginseng Research, 38(4), 276-281.
174. Butt, M. S., Sultan, M. T., & Aziz, M. (2009). Tea and its consumption: Benefits and risks. Critical Reviews in Food Science and Nutrition, 49(6), 463-473.