INTRODUCTION:

Cancer development is the speedy improvement of peculiar cells that develop unusually their normal limitations and which invade adjacent elements of the body parts and affect different organs (metastases) (WHO Cancer Factsheet Feb 2010)¹. Cancer is the main public fitness trouble that affects each evolved and growing country, additionally reasons of morbidity and mortality in every part of the world. Cancer is acquiring the second main motive of death, following coronary heart problems and affecting age groups. Around 8.8 million people are died in 2015 due to cancer.

Reports confirm that due to cancer approximately 70% of people die in low and middle-earning countries. Gradually increasing death rates are recorded in between 2012 to 2018 estimated as 14.1 million to 18.1 million respectively. Expected new cases worldwide are likely to grow 23.6 million in 2030². Commonly, people (Male and female) are affected by numerous forms of cancers like breast cancers, colon cancers or rectal cancers, cancer affected to lungs, skin, liver, pancreatic and prostate cancer^3-5 shown in figure 1 and 2. It can arise at any stage and in any age group of people, so its early detection and remedy can enhance the survival chances of the patient. Considering the sensitivity of the cancer disease, its treatment needs early detection to save the life of the patient. Treatment cost for the cancer is quite high which could affect the economic condition of the county and the individuals as well. There are several techniques are followed in cancer treatment such as surgical dissection, radiation therapy, and chemotherapy, etc.⁶ Different types of cancer mainly treated with chemotherapy is one of the most popular treatment technique⁷. Still, there are some issues are reported in chemotherapy technique like toxicity and adverse reactions. The predominant negative aspects of chemotherapy are recurrence several types of cancer, drug resistance, and producing toxicity to healthy tissues. To conquer the troubles of current therapy, look for new promising anticancer medicines with high therapeutic efficacy and low toxicity. To attain an excellent feasible healing response, a novel technique in drug delivery should be designed.

Nature is an appealing supply of the latest healing entities with animals, plant sources and marine organisms, and microorganisms all contributing medicinal property with the capability in controlling cancer. Plants were traditionally used inside the relief of many illnesses consisting due to cancer with over 60% of presently used anticancer pills derived from herbal sources. Phytochemicals and derivatives obtained from plant sources are promising alternatives to enhance cancer therapy with reduced toxic effects. Phytochemicals, a category of bioactive molecules that may be received from vegies, grains, fruits⁸ and different plant parts, were demonstrated as the appropriate element for cancer therapy. The commonly available anticancer phytoconstituents are vinca alkaloids, paclitaxel (taxol), taxanes and its analogs, podophyllotoxin derivatives, camptothecin derivatives, anthracyclines, berberine, catechins, celastrol, curcumin, quercetin and resveratrol, and lots of others, display promising anticancer pharmacological activities^9-15. Numerous research has proven that those phytochemicals can alter the cell and molecular status including apoptosis, cell proliferation, sequence of cell arrangement, DNA restoration, minimising metastasis^16-18. Most of the phytoconstituents are approved internationally for further development of nanophytoconstituents in cancer therapy^19,20. Phytoconstituents are gradually considered to formulate more effective anticancer agents with low toxicity well tolerated in normal cells proved by in vitro followed by in vivo results.

Fig. 1: Estimation of different types of cancer in all ages of male world wide

Fig. 2: Estimation of different types of cancer in all ages of female world wide

Richard Feynman in 1959 discovered nanotechnology, gradually became famous for its application in drug delivery. Nanotechnology became more popular in medication and formulations of pharmaceuticals in the nano range, commonly enhancing efficacy of drug and clinical potency²¹. The nanoparticles enhance the property of the active drug and significantly increase the drug potency by modifying the composition, particle size, morphology, and surface modification. Nanomedicines also overcome the limitation of phytoconstituents by enhancing the solubility, bioavailability, stability, low toxicity to healthy cells, increase cellular uptake, decreasing dose frequency, and obtaining steady-state drug plasma concentration. Nanoparticles provide better blood stability, the multifunctional layout of nanomedicines, and restrained interaction with improved therapeutic efficacy²². Nanotherapy upon cancer treatment proves better results in comparison with conventional dosage form. Nanotechnology is also useful to increase permeability for water-insoluble drugs⁷, increase its half-life and also protect the drug from GIT²³, specific targeted drug delivery²⁴, and combination drug delivery for better results²⁵. In this regard improvement of the nano-phytoconstituents drug, transport technique is considered as a promising therapy for cancer treatment with low toxicity and side effects on healthy cells.

The goal of this review had been focused on the current development in novel drug delivery system and their therapeutic enhancement to cure cancer by advancement in nanophytoconstituents.

Recent Advancement of Nanotechnology as A Drug Carrier:

A form of Nanoparticles (NPs) in the range of 1 to 100 nm, had been implemented as drug transport systems, because of elevating drug bioavailability, improved therapeutic efficacy, and being considered as a good carrier in targeted drug transport²⁶. A colloidal polymeric matrix is used as a carrier to encapsulate the active constituents²⁷ and targeted to the specific cancerous cell^28,29. There is some specific type of nanoparticles are available like organic nanoparticle conjugates with polymers, polymeric nanocarriers, lipid nanoparticles, some inorganic nanoparticles like carbon nanotubes, magnetic nanoparticles, gold, and silver nanoparticles³⁰ helps to deliver the drug to the targeted site by crossing the several biological barriers. Above discussed nanoparticles provide different structures, shapes, and surface morphology to the final formulation. Nanoparticles used for anticancer drug transport had been accredited through the FDA³¹ and also implemented in biomedical sciences for most of the cancer therapy.

Nanotechnology in Targeted Specific Drug Delivery System:

Targeted drug transport has emerged as an incredible medicinal drug technique for direct action on the infected organ and minimizing the toxicity in patient body. Due to the specific shape, size, and morphology of the nano-drug delivery system, it helps to carry an adequate amount of active drug concentration without side effects and increase the therapeutic efficacy with target-specific³². NPs with a low diameter range are commonly taken into consideration appropriate for most cancers therapy, as they can efficiently supply medicaments and enhance permeability retention (EPR) to the targeted cell. This is regularly predicted because of the deposition of nanomedicines in tumors and is considered as passive diffusion. So the healing of cancer depends on the binding effect of nanomedicines with tumor cells.

Significance of Nanotechnology as Anticancer Agent:

Cancer takes place at a molecular stage whilst more than one subsets of genes go through genetic alterations, both inactivation of tumor cells and activation of oncogenes. Then proliferation occurs in a higher rate in the cancer cells which leads to improper function of affected organs. Tumor tissues are characterized and found growth, migration of cells and changes in endothelial cells actively known as angiogenesis need more blood supply to the affected cell for their growth. With the improvement of nanotechnology, the combination of nonmaterial into most cancers cells is considered as latest technology availed by clinicians. Nanotechnology enhances the treatment methodology and is also considered as the creative technology in material utilization in a nano range. Nanoformulations may be designed to have interaction with the specific cancer cells to inhibit abnormal growth. They constitute new guidelines for greater powerful analysis and remedy for cancer treatment.

Nanophytochemicals as A Cancer Remedy:

Reports confirm that numerous phytoconstituents are already reported for cancer treatment such as taxane diterpenoids, vinca alkaloids, camptothecin derivatives, epipodophyllotoxin, combretastatin, omacetaxine mepesuccinate, cephalotaxine, and ingenol mebutate, etc. Phytoconstituents show very poor solubility, low stability is considered as the major drawback for this compound. These issues controlled by numerous analogs and application of prodrugs and techniques were developed. Nanophytoconstituents is a suitable approaches in treatment of cancer gradually reported by several researchers. In this regard, a brief description of some phytochemicals is discussed which shows anticancer properties.

Vinca Alkaloids:

Madagascar plant is the main source of vinka alkaloids. The main use of vinka alkaloids are to deal with hypoglycemic, excessive blood stress, and cytotoxic activity. It shows anticancer activity in most cancer diseases. There are 4 main vinka alkaloids are reported for its scientific use: vinblastine, vinorelbine, vincristine, and vindesine. Except for vindesine, all the extracts of alkaloids are used for cancer treatment in United States. Vinflunine is likewise a brand new artificial vinca alkaloid, which has been accepted in Europe for the remedy of second-line transitional carcinoma. Vinca alkaloids used as most popular phytochemicals used against most cancers therapy. These alkaloids are generally used with chemotherapy in a combined form to treat several cancers which include leukemia, Hodgkin and non-Hodgkin lymphomas, superior testicular carcinoma, lungs and breast cancer and Kaposi's sarcoma. In this short span, vinflunine is approved for cell carcinoma treatment³³.

Taxanes:

Taxanes derived from yew tree and the bark part of this tree are utilized as anticancer agent. The mitosis of cell is controlled followed by stabilization of microtubules could be an important mechanism behind the taxane treatment against cancer. Paclitaxel and docetaxel, are the two main taxanes without any further modification directly approved in the multiple tumor treatment. Paclitaxel, a herbal product remoted from Taxus bark and leaf. Brevifolia and docetaxel is a semi-synthetic derivative obtained from taxus, is generally utilized in ovarian, lungs, breast, pancrease and prostate cancers therapies. A variety of semisynthetic derivatives was obtained with progressed cytotoxicity in resistant tumors, reduced toxicity, and progressed solubility. Although the Texans differ in their pharmacological activity, toxicity, and clinical impact but found similarities in structure and mechanism action. Taxanes are already used in tumor chemotherapy with the combination of monoclonal antibodies and different cytotoxics.

Camptothecins:

Camptothecin is a quinolone alkaloid remoted from the plant camptotheca acuminate. Numerous camptothecins are reported by the researchers last few decades among them only two derivatives like irinotecan and topotecan approved by FDA for the cancer therapy. Among them, irinotecan is mostly considered for colon cancer and rectum cancer. Similarly, topotecan is used against cervical, ovarian cancer, and lung cancer.

Podophyllotoxins:

Podophyllotoxin is a herbal product obtained from podophyllum peltatum and Podophyllum emodi (Berberidaceae) plants. Podophyllum shows toxicity, and rhizome part are taken for the cancer treatment. Other than cancer also useful in the treatment of jaundice, liver problem, syphilis, fever, loss of hearing. It has the property to kill parasites present in the intestine, helps in bowel movement. The main derivatives are teniposide and etoposide used to obstruct topoisomerase II and also restricted DNA cleavage. Podophyllotoxin shows multidrug-resistant activity during cancer treatment.

Apigenin:

Apigenin used in neck and head squamous molecular carcinoma, glioblastoma cells and triple-bad breast most cancers cells. It exhibit that apigenin indicates selective molecular cytotoxicity to most stem cell of cancers which might be directly related to molecular metastasis, proliferation^34-36. However, consistent with the biopharmaceutics class system, apigenin became categorized as a BCS class II drugs having low solubility which substantially holds returned its use in medical settings³⁷. Hence, to obtain a higher bioavailability, a brand new method is necessary. Apigenin flavonoid is very important due to the application as anti-cancerous therapy, low toxicity, and resistance to oxidation, and anti-inflammatory properties ³⁸. The common source of apigenin is celeriac, celery, parsley and chamomile tea³⁹. Apigenin is especially ample inside the chamomile plant flower, containing up to 68% flavonoids⁴⁰. Apigenin exerts its anticancer activity by inhibiting autophagy and apoptosis⁴¹. Numerous studies carried out on targeting breast cancer cell, head, and squamous cell of neck found that apigenin produces a cytotoxic effect during metastasis, proliferation. Lower solubility of apigenin, make the researchers to develop a better formulation to hinder drawback of the active drug.

Curcumin:

In the year of 1815 curcumin was obtained from Curcuma longa. Scientists discover its antioxidant, antimalarial, anti-inflammatory, antimicrobial, anti-fungal, anti-viral, and anti-cancer properties^42-44. For cancer cells, it is necessary to control their cell growth without hampering healthy cells of the organ. In this regard, it was found that curcumin directly impacts the cancer cell and causes cell apoptosis^45-47. Currently, maximum research focused on the development of the new carrier drug delivery which improves lower bioavailability, low solubility, and low stability of curcumin^48-50.

Lipid-based nanomedicines:

Lipid nanoparticles had been extensively used in the pharmaceutical enterprise for decades. Compared with conventional drug delivery system lipid-based nanomedicines are easier and more effective and shows better therapeutic efficacy. Frequently used lipid-based nanoparticles are liposomes, nanodiscs, solid lipid nanoparticles (SLNs), nano lipid carriers, lipid micelles and a lipid-based hybrid form of nanoparticles have recognized as a novel cancer therapy. In case of lipid-based nanoparticle, it was found that it enhances stability, biocompatibility, biodegradability and allow the hydrophilic and hydrophobic drug to penetrate the biological membranes⁵¹. The surface property of lipid nanoparticles can be easily modified based on the targeted site by using different ligands. It also enhances the pharmacokinetic property of an active drug by targeting it to the affected cells of the tumor. It doesn't create any harmful effect on the healthy cells and produces more stable molecules as well⁵².

Future Perspectives of Nanophytoconstituents:

The current review article mainly focused on the phytochemical and their significance on different cancer treatments. As it is confirmed through several kinds of literature that cancer is considered to be one of the leading reasons for death worldwide. Conventional methods are available to treat, but it was found that the treatment process is quite painful, produces a toxic effect on the patient's body, and is costly. So this current review mainly focused on phytoconstituents and their promising aspects in the field of cancer therapy. To overcome the drawback available with the phytochemicals could be minimized by introducing nanotechnology. Nanotechnology in the field of cancer treatment played an important role to minimize the low stability, poor solubility, fewer bioavailability issues that arise by phytoconstituents. Also, nanophytoconstituents can produce safe, low toxic, fewer side effects, and low-cost medicine in the market for the treatment of cancer. Regardless numerous methods have been developed in the research field towards further development in large-scale production approved by regulatory bodies. Phytochemicals are encapsulated in nanoparticles which are considered a good carrier for the targeted drug delivery in a different type of cancer treatment. Nanoparticles with altered surface morphology were helpful in the penetration of the medicines through different biological barriers and reached the targeted site. Due to the smaller size of the nanoparticles, it increases the surface area and helps to retard the drug release up to a predetermined time. So nanophytoconstituent is considered to be a novel therapy in cancer treatment as compared to conventional methods available so far.

CONCLUSION:

A wide range of drug delivery system is used to treat different type of cancer, but due to its limitation scientists now focused on the development of novel drug delivery systems which helps to provide potential anticancer agents. There has been increasing interest was observed in the formulation of nanophytoconstituents which could be used to improve chemical stability, low solubility, poor bioavailability of the natural products, and help in targeted specific cancer treatment. The drug release profile and therapeutic efficacy of the phytoconstituents could be enhanced by encapsulating the active constituents inside the nanocarriers. Different types of nanoparticles are available to treat cancer based on their specific application. These nanophytoconstituents could be a better substitute as compared to conventional dosage forms available for cancer therapy. Nanotechnology-based phytochemical delivery for selective drugs has shown better pharmacokinetic parameters and low toxicity towards the cancer-treated patient. Modified surface property based on the selective ligands helps the drug to reach the targeted area and produce its therapeutic impact. The authors tried to bring to the notice of all the clinicians that the ongoing effort on nanophytoconstituents by the research scientist could open up a new chemotherapeutic regimen in cancer treatment that would be commercialized sooner.

ACKNOWLEDGEMENT:

The authors thanks the management of Dr. M.G.R. Educational and Research Institute for their continuous support

CONFLICT OF INTEREST:

No conflict of interest in authors.

REFERENCES:

1. Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends in cell biology. 2019;29(3):212-26. https://doi.org/10.1016/j.tcb.2018.12.001

2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer j clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492

3. Menon S, Agarwal H, Rajeshkumar S, Kumar SV. Anticancer assessment of biosynthesized silver nanoparticles using Mucuna pruriens seed extract on Lung Cancer Treatment. Res J Pharm Tech. 2018;11(9):3887-91. DOI : 10.5958/0974-360X.2018.00712.6

4. Li B, Gao MH, Chu XM, Teng L, Lv CY, Yang P, Yin QF. The synergistic antitumor effects of all-trans retinoic acid and C-phycocyanin on the lung cancer A549 cells in vitro and in vivo. Eur j pharm. 2015;749:107-14. https://doi.org/10.1016/j.ejphar.2015.01.009

5. Sumithra S, Vadivu R, Radha R. Colon Targeted Drug Delivery System of Phytoconstituents. Res J Pharm Tec. 2019;12(7):3144-50. DOI : 10.5958/0974-360X.2019.00530.4

6. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer research. 2008 Nov 1;68(21):8643-53. DOI: 10.1158/0008-5472.CAN-07-6611 Published November 2008

7. Przystupski D, Niemczura MJ, Górska A, Supplitt S, Kotowski K, Wawryka P, Rozborska P, Woźniak K, Michel O, Kiełbik A, Bartosik W. In search of panacea—review of recent studies concerning nature-derived anticancer agents. Nutrients. 2019;11(6):1426. https://doi.org/10.3390/nu11061426

8. Pandian RS, Noora AT. GC-MS Analysis of Phytochemical Compounds Present in the Leaves of Citrus medica. L. Res J Pharm Tec. 2019;12(4):1823-6. DOI : 10.5958/0974-360X.2019.00304.4

9. Pavithra RP, Jayashri P. Influence of naturally occurring phytochemicals on oral health. Research Journal of Pharmacy and Technology. 2019;12(8):3979-83. DOI : 10.5958/0974-360X.2019.00685.1

10. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218-20. DOI: 10.1126/science.275.5297.218

11. Kabary DM, Helmy MW, Abdelfattah EZ, Fang JY, Elkhodairy KA, Elzoghby AO. Inhalable multi-compartmental phospholipid enveloped lipid core nanocomposites for localized mTOR inhibitor/herbal combined therapy of lung carcinoma. Eur J Pharm Biopharm. 2018;130:152-64. https://doi.org/10.1016/j.ejpb.2018.06.027

12. Kashyap D, Sharma A, Tuli HS, Sak K, Punia S, Mukherjee TK. Kaempferol–A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements. J functional foods. 2017;30:203-19. https://doi.org/10.1016/j.jff.2017.01.022

13. Karpagam T, Firdous J, Priya S, Varalakshmi B, Gomathi S, Geetha S, Muhamad N. Anti-Cancer Activity of Aloe Vera Ethanolic Leaves Extract against In vitro Cancer Cells. Res J Pharm Tec. 2019;12(5):2167-70. DOI : 10.5958/0974-360X.2019.00360.3

14. Susmi MS, Kumar RS, Sreelakshmi V, Menon SV, Mohan S, Suja ST, Manakadan AA. A Computational approach for identification of Phytochemicals for targeting and optimizing the inhibitors of Heat shock proteins. Res J Pharm Tec. 2015;8(9):1199-204. DOI : 10.5958/0974-360X.2015.00219.X

15. Wang H, Zhu W, Huang Y, Li Z, Jiang Y, Xie Q. Facile encapsulation of hydroxycamptothecin nanocrystals into zein-based nanocomplexes for active targeting in drug delivery and cell imaging. Acta biomater. 2017;61:88-100. https://doi.org/10.1016/j.actbio.2017.04.017

16. Lall RK, Syed DN, Adhami VM, Khan MI, Mukhtar H. Dietary polyphenols in prevention and treatment of prostate cancer. Int j molecular sci. 2015;16(2):3350-76. https://doi.org/10.3390/ijms16023350

17. DiMarco-Crook C, Xiao H. Diet-based strategies for cancer chemoprevention: the role of combination regimens using dietary bioactive components. Annual review of food sci tech. 2015;6:505-26. https://doi.org/10.1146/annurev-food-081114-110833

18. Ruiz RB, Hernández PS. Cancer chemoprevention by dietary phytochemicals: Epidemiological evidence. Maturitas. 2016;94:13-9. https://doi.org/10.1016/j.maturitas.2016.08.004

19. Bhanot A, Sharma R, Noolvi MN. Natural sources as potential anti-cancer agents: A review. Int j phytomed. 2011;3(1):09.

20. Sheng-Nan S, Chao W, Zan-Zan Z, Yang-Long H, Venkatraman SS, Zhi-Chuan X. Magnetic iron oxide nanoparticles: Synthesis and surface coating techniques for biomedical applications. Chinese Physics B. 2014;23(3):037503. https://doi.org/10.1088/1674-1056/23/3/037503

21. Reddy JM, Anitha R, Rajeshkumar S, Lakshmi T. Characterisation of Cumin oil mediated silver nanoparticles using UV-visible spectrophotometer and TEM. Res J Pharm Tec. 2019;12(10):4931-3.

22. Bhadoriya SS, Mangal A, Madoriya N, Dixit P. Bioavailability and bioactivity enhancement of herbal drugs by “Nanotechnology”: a review. J Curr Pharm Res. 2011;8:1-7.

23. Navya PN, Kaphle A, Srinivas SP, Bhargava SK, Rotello VM, Daima HK. Current trends and challenges in cancer management and therapy using designer nanomaterials. Nano Convergence. 2019;6(1):1-30. https://doi.org/10.1186/s40580-019-0193-2

24. Duan X, Li Y. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small. 2013;9(9‐10):1521-32. https://doi.org/10.1002/smll.201201390

25. Rawal S, Patel MM. Threatening cancer with nanoparticle aided combination oncotherapy. J controlled release. 2019;301:76-109. https://doi.org/10.1016/j.jconrel.2019.03.015

26. Kalyankar TM, Butle SR, Chamwad GN. Application of nanotechnology in cancer treatment. Res J Pharm Tech. 2012;5(9):1161-7.

27. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug discovery today. 2003;8(24):1112-20. https://doi.org/10.1016/S1359-6446(03)02903-9

28. Parveen S, Sahoo SK. Polymeric nanoparticles for cancer therapy. Journal of drug targeting. 2007;16(2):108-23. https://doi.org/10.1080/10611860701794353

29. Haque SE, Sheela A. Development of polymer-bound fast-dissolving metformin buccal film with disintegrants. Int j nanomed. 2015;10(Suppl 1):199. doi: 10.2147/IJN.S80052

30. Menon S, Agarwal H, Rajeshkumar S, Kumar SV. Anticancer assessment of biosynthesized silver nanoparticles using Mucuna pruriens seed extract on Lung Cancer Treatment. Res J Pharm Tec. 2018;11(9):3887-91. DOI : 10.5958/0974-360X.2018.00712.6

31. Qiu LY, Bae YH. Polymer architecture and drug delivery. Pharm Res. 2006;23(1):1-30. https://doi.org/10.1007/s11095-005-9046-2

32. Barahuie F, Dorniani D, Saifullah B, Gothai S, Hussein MZ, Pandurangan AK, Arulselvan P, Norhaizan ME. Sustained release of anticancer agent phytic acid from its chitosan-coated magnetic nanoparticles for drug-delivery system. Int j nanomed. 2017;12:2361. doi: 10.2147/IJN.S126245

33. Martino E, Casamassima G, Castiglione S, Cellupica E, Pantalone S, Papagni F, Rui M, Siciliano AM, Collina S. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorganic and medicinal chemistry letters. 2018;28(17):2816-26. https://doi.org/10.1016/j.bmcl.2018.06.044

34. Kim B, Jung N, Lee S, Sohng JK, Jung HJ. Apigenin inhibits cancer stem cell‐like phenotypes in human glioblastoma cells via suppression of c‐met signaling. Phytotherapy Res. 2016;30(11):1833-40. https://doi.org/10.1002/ptr.5689

35. Li YW, Xu J, Zhu GY, Huang ZJ, Lu Y, Li XQ, Wang N, Zhang FX. Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Cell death discovery. 2018;4(1):1-9. https://doi.org/10.1038/s41420-018-0124-8

36. Ketkaew Y, Osathanon T, Pavasant P, Sooampon S. Apigenin inhibited hypoxia induced stem cell marker expression in a head and neck squamous cell carcinoma cell line. Archives of oral biology. 2017;74:69-74. https://doi.org/10.1016/j.archoralbio.2016.11.010

37. Zhang J, Liu D, Huang Y, Gao Y, Qian S. Biopharmaceutics classification and intestinal absorption study of apigenin. Int j pharm. 2012;436(1-2):311-7. https://doi.org/10.1016/j.ijpharm.2012.07.002

38. Madunić J, Madunić IV, Gajski G, Popić J, Garaj-Vrhovac V. Apigenin: A dietary flavonoid with diverse anticancer properties. Cancer letters. 2018;413:11-22. https://doi.org/10.1016/j.canlet.2017.10.041

39. The compound in the Mediterranean diet that makes cancer cells 'mortal' Emily Caldwell, Medical Express, May 20, 2013.

40. Venigalla M, Gyengesi E, Münch G. Curcumin and Apigenin–novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease. Neural Reg Res. 2015;10(8):1181. doi: 10.4103/1673-5374.162686

41. Yan X, Qi M, Li P, Zhan Y, Shao H. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell and bioscience. 2017;7(1):1-6. https://doi.org/10.1186/s13578-017-0179-x

42. Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Molecular cancer. 2011;10(1):1-9. https://doi.org/10.1186/1476-4598-10-12

43. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. The molecular targets and therapeutic uses of curcumin in health and disease. 2007:1-75. DOI: 10.1007/978-0-387-46401-5_1

44. Yadav AR, Mohite SK. Cancer-A silent killer: An overview. Asian J Pharm Res. 2020;10(3):213-6. DOI : 10.5958/2231-5691.2020.00036.2

45. Kunnumakkara AB, Bordoloi D, Harsha C, Banik K, Gupta SC, Aggarwal BB. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clinical Sci. 2017;131(15):1781-99. https://doi.org/10.1042/CS20160935

46. Novitasari D, Jenie RI, Wulandari F, Utomo RY, Putri DD, Kato JY, Meiyanto E. Curcumin-like structure (CCA-1.1) induces permanent mitotic arrest (Senescence) on Triple-negative breast cancer (TNBC) cells, 4T1. Res J Pharm Tec. 2021;14(8):4375-82. DOI: 10.52711/0974-360X.2021.00760

47. Rahmani AH, Al Zohairy MA, Aly SM, Khan MA. Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Bio Med Res Int. 2014 Oct;2014. https://doi.org/10.1155/2014/761608

48. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Molecular pharm. 2007;4(6):807-18. https://doi.org/10.1021/mp700113r

49. Jankun J, Wyganowska-Świątkowska M, Dettlaff K, Jelińska A, Surdacka A, Wątróbska-Świetlikowska D, Skrzypczak-Jankun E. Determining whether curcumin degradation/condensation is actually bioactivation. Int j molecular med. 2016;37(5):1151-8. https://doi.org/10.3892/ijmm.2016.2524

50. Shen L, Ji HF. The pharmacology of curcumin: is it the degradation products?. Trends in molecular med. 2012;18(3):138-44. https://doi.org/10.1016/j.molmed.2012.01.004

51. Gurushankar K, Gohulkumar M, Prasad NR, Krishnakumar N. Synthesis, characterization and in vitro anti-cancer evaluation of hesperetin-loaded nanoparticles in human oral carcinoma (KB) cells. Advances in Natural Sciences: Nano Nanotech. 2013;5(1):015006. https://doi.org/10.1088/2043-6262/5/1/015006

52. L Arias J, Clares B, E Morales M, Gallardo V, A Ruiz M. Lipid-based drug delivery systems for cancer treatment. Current drug targets. 2011;12(8):1151-65. DOI: https://doi.org/10.2174/138945011795906570

Received on 29.10.2021 Modified on 24.12.2021

Research J. Pharm. and Tech 2023; 16(1):447-452.

DOI: 10.52711/0974-360X.2023.00076