INTRODUCTION:

A leading cause of death worldwide and one of the most significant diseases of the twenty-first century, cancer has its own molecular signature for each type. One of the main cancer treatment options is chemotherapy, which employs molecules that can block angiogenesis, replicative immortality mechanisms, proliferative signaling pathways, and apoptosis in tumor cells^1-2. Depending on a number of variables, including the type of cancer and the patients' underlying biological conditions, it typically consists of either a single therapy or a combination of conventional treatments.

The pharmacological dogma of "one drug-one target" has been the foundation of the traditional method of treatment for many diseases known as monotherapy.

However, combined therapies outperformed single-drug-based therapies by a wide margin³.

The synergistic effect, which can be defined as an increase in efficacy for a combination of components when compared to a single one, is the most significant characteristic of combined therapies. Chemotherapy fails due to side effects, drug resistance, and target specificity even though anticancer research and drug discovery are constantly expanding the therapeutic arsenal^4-8.

One of the most difficult aspects of chemotherapy is still drug resistance, which is caused by a number of variables related to the therapy, cancer cell population, and host environment^9-13. Therapeutic pressure, tumor burden, growth and heterogeneity, physical barriers, immune system, and undruggable genome were the main determinants of drug resistance as outlined. Higher doses must be used in order to produce a tumoricidal effect comparable to the initial dosage when cancer drug resistance develops, increasing the likelihood of serious side effects^14-16. Drug influx or efflux, DNA damage repair, cell death inhibition, drug inactivation, epithelial-to-mesenchymal transition, drug target alteration, NF-B activation, and STAT-3 activation are the molecular mechanisms of chemoresistance. Chemosensitization is the process of enhancing the tumor-killing effects of chemotherapeutic drugs. Chemosensitizers that have the ability to accumulate, preferably within the tumor site, and potentialize systemic conventional therapeutic effects may therefore be candidates for use in combating drug resistance. Previous research has shown that plant components can enhance the efficacy of conventional chemotherapy by prolonging the time that chemotherapeutics remain inside tumor cells, causing cell death by up-regulating pro-apoptotic targets, encouraging DNA damage, or controlling the expression of altered and unaltered drug targets. These mechanisms make anticancer medications more cytotoxic, encouraging a synergistic effect even in cells with developed resistance. As a result, they can make drugs more effective at lower doses while decreasing their toxicity. Among the potential chemosensitizers are natural substances like phenolic derivatives, flavonoids, alkaloids, carotenoids, terpenoids, quinones, saponins, and steroids^17-18.

METHODS:

Materials:

Clinical trials access and the transition from in vitro to in vivo testing take time and a lot of resources. Using methods created by the Organization for Economic Co-operation and Development (OECD) and the correlation of high-speed screening, biological phenotyping, and integration with computer modeling in a new approach to the toxicological system, the time needed for toxicological testing, a crucial step, has been decreased as a result of technological advancements.Clinical trials are implemented based on the achievement of the dose with a therapeutic effect of the dose because in vitro studies require less complicated procedures than in vivo studies. Unfortunately, access to a molecule during the clinical trial phase depends primarily on financial factors at this time, with the majority of studies being stopped due to a lack of funding. Additionally, few isolated natural products are actually developed into clinically effective drugs and promising preclinical results frequently do not translate to success in clinical trials^15-19.

Apigenin, quercetin, luteolin, and genistein are some examples of flavonoid compounds that have significant potential for preventing cancer. A natural phenolic substance called apigenin is a flavone that can be found in many plants, including some vegetables and medicinal species like Lycopodium clavatum L. and Petroselinum crispum L^20-24. In terms of pharmacology, it has been shown to be an effective substance in DNA protection against UVB-induced damage using a variety of mechanistic techniques, including the removal of the cyclobutane rings, the inhibition of ROS production, and the down-regulation of NF-B. Additionally, apigenin has anti-inflammatory and anti-proliferative qualities. Apigenin reduces the proliferation and carcinogenesis of breast cells that are triggered by inflammation by inhibiting the expression of COX-2, inducible nitric oxide synthase (iNOS), and nitric oxide (NO)^25-26.

Additionally, this phytochemical is in charge of inhibiting the Wnt/-catenin signaling pathway, an essential signaling cascade involved in critical biological processes. This pathway's dysregulation is frequently linked to a number of illnesses, including cancer. According to the proposed mechanism for this specific activity, apigenin inhibits tankyrase 2 (TNK2), an enzyme in charge of telomere length regulation, vesicle trafficking, and activation of the Wnt signaling pathway^27-29. According to the study, apigenin and other flavones target TNK2's nicotinamide binding site.By binding to the progesterone receptor, apigenin acts as a progesterone agonist and as an inhibitor of the autocrine-paracrine-regulated metastatic processes, such as angiogenesis, migration, invasion, and adhesion through the reversal of the epithelial-mesenchymal transition. Apigenin has been shown to be a pro-apoptotic compound in terms of its effect on cancer cells³⁰.

Natural Compound	Cancer Type	Animal Model	Dose/Administration	Findings
Resveratrol	Breast cancer	MDA-MB-231 cells xenograft model in female athymic mice	intraperitoneal administration of 25 mg/kg/day of resveratrol (ethanolic solution) for 3 weeks	↓ tumor size; ↑ apoptotic index; ↓ angiogenesis
	Lung cancer	A/J mice with 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone-induced lung carcinogenesis	intranasal administration of ~60 mg/kg three times a week for 25 weeks	↓ tumor size (27%); ↓ tumor volume (45%) chemopreventive properties in the chemically induced lung cancer
	Melanoma	B16F10 cells xenograft model in female C57BL/6 mice	intravenous administration of 0.5 mg/kg of resveratrol (PBS solution) 6 times on days −2, 0, 2, 4, 6, and 8	inhibition of tumor growth and metastasis; ↑ NK cell activity
Curcumin	Breast Cancer	HER-2-overexpressed BT-474 xenograft mod-el in female athymic nude mice	intraperitoneal administration of curcumin dissolved in 0.1% DMSO at a dose of 45 mg/kg twice/week for 4 consecutive weeks	↓ tumor volume (by 76.7%)
	Cervical Cancer	Human cervical cancer HeLa cells xenograft model in nude mice	intraperitoneal administration of curcumin at a dosage of 50, 100 and 200 mg/kg, once/two days for 20 days	↓ tumor volume and mass; tumor inhibition rate percentages were 1.7%, 31.1% and 39.6% for curcumin 50, 100 and 200, respectively
	Colon Cancer	HCT-116 Cells Xeno-graft model in female homozygous ICR SCID mice	500 mg/kg body by gavage every day for 3 weeks	↓ growth of p53-positive (wt) and p53-negative colon cancer HCT-116 cells; ↓ proliferation and ↑ apoptosis accompanied by the attenuation of NF-κB activity; synergistic effect with resveratrol
EGCG	Colorectal Cancer	Orthotopic colorectal cancer xenograft model in BALB/c nude mice	intragastrical administration of 5, 10 and 20 mg/kg of EGCG once daily for 14 days	↓ tumor volume; ↑ apoptotic rates for EGCG 5, 10, and 20 mg/kg (38.04%, 51.87%, 52.27%, and 54.33%)
	Lung Cancer	A549 cells xenograft model in BALB/c nude male mice	0.05% EGCG solutions in DMSO administered in drinking water daily for 13–21 days	↓ tumor growth; ↓ angiogenesis and CD34 positive vessels
	Breast Cancer	MCF-7 cells xenograft model in female CB-17 severe combined im-munodeficient mice	100 mg/kg of EGCG dissolved in 100 μL water every 2 days by oral gavage	↓ tumor growth; ↓ expression of miR-25; ↓ Ki-67 and ↑ pro-apoptotic PARP expression
Quercetin	Pancreatic Cancer	MIA PaCa-2 cells Orthotopic xenograft model in nude mice	1% quercetin -supplemented diet for 42 days (Oral administration)	↓ tumor volume and weight; ↓ tumor cell proliferation; ↑ apoptotic cell death
Rutin	Colon Cancer	SW480 cells xenograft in nu/nu mice	daily intraperitoneal administration of rutin at different doses (≤ 20 mg/kg) for 32 days	↓ tumor volume and weight; ↑ mean survival time by 50 days; ↓ VEGF serum levels (by 55%)
Betulinic acid	Colorectal cancer	HCT116 cells xenograft model in mice	daily intraperitoneal administration of 10 and 20mg/kg/day of betulinic acid for 21 days	↓ tumor growth; ↓ number of Ki67-positive and MMP-2-positive cells; ↑ cleaved caspase-3-positive cells
Artemisinin (Artesunate)	Breast Cancer	4T1 cells xenograft model in female BALB/c mice	intraperitoneal injection with 100 mg/kg artemisinin dissolved in a 0.2% DMSO solution) daily, for 20 days	↓ Treg and MDSC expansion in the spleen and tumor; ↑ percentages of CD4 + IFN-γ + T cells; ↑ FN-γ and TNF-α
	Colorectal Cancer	CLY cells xenograft model in female athymic nude mice (Balb/c nu/nu)	intravenous administration of artesunate as follows: (1) intermittent large dose treatment (300 mg/kg; every 3 days, for 7 days) and (2)persistent small dose treatment (100 mg/kg; every day, for 20 days)	slow growth of tumor xenografts; ↓ physiological activity of tumor xenografts; delayed spontaneous liver metastasis.
	Cervical Cancer	HeLa cells xenografts in male BALB/c mice	intraperitoneal administration of 100 mg/kg/day artesunate for 7 days	↓ microvessel density; ↑ apoptosis; ↑ Cyclin B1 expression G2-M phase arrest; ↑ radio-sensitivity
Ginseng	Breast Cancer	MCF-7 cells xenograft model in female BALB/c athymic nude mice	intravenous administration of Ginseng extract (50 or 100 mg/kg), once a day for 4 weeks	↓ tumor weight; ↑ Bax, cleaved caspase-3, and cleaved PARP; ↓ Bcl-2
Ginseng	Lung Cancer	LLC-1 cells xenograft model in male C57BL/6J mice	Asian Ginseng extract (0.25, 0.5, and 1 g/kg/day) daily administration as pretreatment (for 10 days) and treatment (for 20 days)	↓ tumor volume and mass; ↓ cell proliferative index; ↓ P-Stat3 and PCNA

CONCLUSION:

The discovery of new structures that can be approved as therapeutically agents for a variety of human diseases is supported by the discovery of natural compounds, which are still regarded as an endless source of models in the search for new active chemotherapeutic agents. Even though a significant number of natural compounds demonstrate therapeutically efficacy in preclinical studies, their number dramatically drops until they enter the clinical trial phase. It is still difficult for researchers to choose the best in vitro and in vivo models that demonstrate the efficacy of natural compounds and guarantee their inclusion in clinical trials. Alternative in vitro and in silico methods that can drastically cut the time and expense needed for in vivo studies should be proposed in order to address these liabilities. These methods should also concentrate resources, particularly financial ones, on the study of biocompounds in clinical trials. The low bioavailability of natural compounds typically limits their efficacy. As a result, in addition to the compound's effectiveness, which is of great interest, researchers must concentrate on drug delivery systems that can address the compound's pharmacokinetic problems and the investigation of suitable derivatives that offer a number of advantages in terms of biological availability and efficacy^31-37.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

REFERENCES:

1. Arjun Patidar, S.C. Shivhare, Umesh Ateneriya, Sonu Choudhary. A Comprehensive Review on Breast Cancer. Asian J. Nur. Edu. & Research. 2012; 2(1): 28-32.

2. Sampoornam. W. Stress and Quality of Life among Breast Cancer Patients. Asian J. Nur. Edu. & Research. 2014; 4(3): 325-327.

3. Jeenath Justin Doss K.. Effectiveness of Foot Massage on Level of Pain among Patients with Cancer. Asian J. Nur. Edu. & Research. 2014; 4(2): 228-231.

4. S. Lavanya, Nalini Jeyavantha Santha, Gowri Sethu. A descriptive study to assess the level of stress among women with selected type of cancer in Erode Cancer Centre at Erode. Asian J. Nur. Edu. & Research. 2014; 4(3): 321-324.

5. Sedigheh Iranmanesh, Ala Shamsi. The Relationship between Type of Cancer and Parent's Psychosocial Risks. Asian J. Nur. Edu. and Research. 2014; 4(4): 495-501.

6. Jasmine Kaur. An Exploratory Study to Assess the Quality of Life among Cancer Patients of District Bathinda, Punjab. Asian J. Nur. Edu. and Research. 2015; 5(1): 18-22.

7. A Study to Assess the Effectiveness of Warm Foot Bath on Sleep Onset Time among Cancer Patients with Insomnia in Nath Lal Parekh Cancer Hospital at Rajkot. Asian J. Nur. Edu. and Research. 2017; 7(2): 231-234.

8. Sheeba Chellappan, Rajamanickam Rajkumar, Merlin Jeyapal. Cancer Pain Management: Teaching Program for Terminally ill Cancer Patients. Asian J. Nur. Edu. and Research. 2017; 7(2): 151-154.

9. Kritika Sharma, Raman Kalia, Manpreet, Shaveta Sharma. A Descriptive Study to Assess the Health Profile and Warning Signs of Cancer among adults Residing in Selected Rural areas of District Roopnagar Punjab. Asian J. Nursing Education and Research. 2018; 8(3):371-374.

10. Gautam, Y., Dwivedi, S., Srivastava, A., Hamidullah, Singh, A., Chanda, D., Singh, J., Rai, S., Konwar, R., Negi, A.S. 2-(3′,4′-Dimethoxybenzylidene)tetralone induces anti-breast cancer activity through microtubule stabilization and activation of reactive oxygen species. RSC Adv. 2016; 6: 33369–33379.

11. Hamid, A.A., Hasanain, M., Singh, A., Bhukya, B., Omprakash, Vasudev, P.G., Sarkar, J., Chanda, D., Khan, F., Aiyelaagbe, O.O., Negi, A.S., Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin. Steroids. 2014; 87: 108–118.

12. Hamid, A.A., Kaushal, T., Ashraf, R., Singh, A., Chand Gupta, A., Prakash, O., Sarkar, J., Chanda, D., Bawankule, D.U., Khan, F., Shanker, K., Aiyelaagbe, O.O., Negi, A.S. (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids. 2017; 119: 43–52.

13. Jain, S., Singh, A., Khare, P., Chanda, D., Mishra, D., Shanker, K., Karak, T. Toxicity assessment of Bacopa monnieri L. grown in biochar amended extremely acidic coal mine spoils. Ecological Engineering. 2017; 108: 211–219.

14. Khwaja, S., Fatima, K., Hasanain, M., Behera, C., Kour, A., Singh, A., Luqman, S., Sarkar, J., Chanda, D., Shanker, K., Gupta, A.K., Mondhe, D.M., Negi, A.S. Antiproliferative efficacy of curcumin mimics through microtubule destabilization. European Journal of Medicinal Chemistry. 2018; 151: 51–61.

15. Kumar, B.S., Ravi, K., Verma, A.K., Fatima, K., Hasanain, M., Singh, A., Sarkar, J., Luqman, S., Chanda, D., Negi, A.S. Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition. Bioorganic and Medicinal Chemistry. 2017; 25: 1364–1373.

16. Mishra, D., Jyotshna, Singh, A., Chanda, D., Shanker, K., Khare, P. Potential of di-aldehyde cellulose for sustained release of oxytetracycline: A pharmacokinetic study. International Journal of Biological Macromolecules. 2019; 136: 97–105.

17. Sathish Kumar, B., Kumar, A., Singh, J., Hasanain, M., Singh, A., Fatima, K., Yadav, D.K., Shukla, V., Luqman, S., Khan, F., Chanda, D., Sarkar, J., Konwar, R., Dwivedi, A., Negi, A.S. Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization. European Journal of Medicinal Chemistry. 2014a; 86: 740–751.

18. Sathish Kumar, B., Singh, Aastha, Kumar, A., Singh, J., Hasanain, M., Singh, Arjun, Masood, N., Yadav, D.K., Konwar, R., Mitra, K., Sarkar, J., Luqman, S., Pal, A., Khan, F., Chanda, D., Negi, A.S. Synthesis of neolignans as microtubule stabilisers. Bioorganic & Medicinal Chemistry. 2014b; 22: 1342–1354.

19. Singh, A., Mohanty, I., Singh, J., Rattan, S. BDNF augments rat internal anal sphincter smooth muscle tone via RhoA/ROCK signaling and nonadrenergic noncholinergic relaxation via increased NO release. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2020; 318: G23–G33.

20. Singh, A., Rattan, S. BDNF rescues aging-associated internal anal sphincter dysfunction. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2021; 321: G87–G97.

21. Singh, A., Singh, J., Rattan, S. Evidence for the presence and release of BDNF in the neuronal and non‐neuronal structures of the internal anal sphincter. Neurogastroenterology and Motility. 2021.

22. Singh, Aastha, Fatima, K., Singh, Arjun, Behl, A., Mintoo, M.J., Hasanain, M., Ashraf, R., Luqman, S., Shanker, K., Mondhe, D.M., Sarkar, J., Chanda, D., Negi, A.S. Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule. European Journal of Pharmaceutical Sciences. 2015; 76: 57–67.

23. Singh, Aastha, Fatima, K., Srivastava, A., Khwaja, S., Priya, D., Singh, Arjun, Mahajan, G., Alam, S., Saxena, A.K., Mondhe, D.M., Luqman, S., Chanda, D., Khan, F., Negi, A.S. Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer. Chem Biol Drug Des. 2016; 88: 625–634.

24. Manmohan, S., Arjun, S., Khan, S. P., Eram, S., & Sachan, N. K., Green chemistry potential for past, present and future perspectives. International Research Journal of Pharmacy. 2021; 3: 31-36.

25. Singh, A., R. Sharma, K. M. Anand, S. P. Khan, and N. K. Sachan. Food-drug interaction. International Journal of Pharmaceutical & Chemical Science. 2012; 1(1): 264-279.

26. Arjun Singh. A Review of various aspects of the Ethnopharmacological, Phytochemical, Pharmacognostical, and Clinical significance of selected Medicinal plants. Asian Journal of Pharmacy and Technology. 2022; 12(4): 349-0. doi: 10.52711/2231-5713.2022.00055

27. Devender Paswan, Urmila Pande, Alka Singh, Divya Sharma, Shivani Kumar, Arjun Singh. Epidemiology, Genomic Organization, and Life Cycle of SARS CoV-2. Asian Journal of Nursing Education and Research. 2023; 13(2):141-4.

28. Arjun Singh, Rupendra Kumar, Sachin Sharma. Natural products and Hypertension: Scope and role in Antihypertensive Therapy. Asian Journal of Nursing Education and Research. 2023; 13(2): 162-6.

29. Arjun Singh. A Review of various aspects of the Ethnopharmacological, Phytochemical, Pharmacognostical, and Clinical significance of selected Medicinal plants. Asian Journal of Pharmacy and Technology. 2022; 12(4): 349-360. doi: 10.52711/2231-5713.2022.00055

30. Arjun Singh, Rupendra Kumar. An Overview on Ethnopharmacological, Phytochemical, and Clinical Significance of Selected Dietary Polyphenols. Asian Journal of Research in Chemistry. 2023; 16(1):8-2.

31. Arjun Singh. Plant-based Isoquinoline Alkaloids: A Chemical and Pharmacological Profile of Some Important Leads. Asian Journal of Research in Chemistry. 2023; 16(1):43-8.

32. Arjun Singh. Withania somnifera (L.) Ashwagandha: A Review on Ethnopharmacology, Phytochemistry, Biomedicinal and Traditional uses. Asian Journal of Pharmacy and Technology. 2023; 13(3):213-7. doi: 10.52711/2231-5713.2023.00038

33. Kaman Kumar, Pooja Singh, Divya Sharma, Akanksha Singh, Himanshu Gupta, Arjun Singh. Prospective Current Novel Drug Target for the Identification of Natural Therapeutic Targets for Alzheimer's Disease. Asian Journal of Pharmacy and Technology. 2023; 13(3):171-4. doi: 10.52711/2231-5713.2023.00030

34. Arijita Singla, Varsha Singh, Komal Kumari, Sonam Pathak, Arjun Singh. Natural Marine Anticancer compounds and their derivatives used in Clinical Trials. Asian Journal of Pharmacy and Technology. 2023; 13(3):235-9. doi: 10.52711/2231-5713.2023.00042

35. Arjun Singh. An Overview on Phytoestrogen based antihypertensive agent for their potential Pharmacological Mechanism. Research Journal of Pharmaceutical Dosage Forms and Technology. 2023; 15(3):211-4. doi: 10.52711/0975-4377.2023.00034

36. Singh, A., Chanda, D., & Negi, A. S. (2018). Antihypertensive activity of Diethyl-4, 4'-dihydroxy-8, 3'-neolign-7, 7'-dien-9, 9'-dionate through increase in intracellular cGMP level and blockade of calcium channels (VDCC) and opening of potassium channel and in vivo models (SHRs and L-NAME induced hypertension). In Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (The 18th World Congress of Basic and Clinical Pharmacology) (pp. PO1-2). Japanese Pharmacological Society.

37. Tim F. Dorweiler, Arjun Singh, Richard N Kolesnick, Julia V. Busik; Inhibition of ceramide rich platforms by anti-ceramide immunotherapy prevents retinal endothelial cell damage and the development of diabetic retinopathy.. Invest. Ophthalmol. Vis. Sci. 2023; 64(8): 941.

Received on 24.12.2022 Modified on 16.05.2023

Asian J. Research Chem. 2024; 17(1):50-54.

DOI: 10.52711/0974-4150.2024.00010