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Recent Patents on Anti-Cancer Drug Discovery

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ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

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Research Article

The Dichloromethane Fraction of Vernonia cinerea Impart Pro-Apoptotic, Genotoxic, Cell Cycle Arrest, and Drug Efflux Inhibitory Effects on Human Adenocarcinoma Cells

Author(s): Asmy Appadath Beeran, Nayanabhirama Udupa and Naseer Maliyakkal*

Volume 15, Issue 3, 2020

Page: [239 - 256] Pages: 18

DOI: 10.2174/1574892815999200824122723

Price: $65

Abstract

Background: Vernonia cinerea (VC) is an important medicinal plant used in the indigenous system of therapy. In ethnomedicine, VC has demonstrated anticancer properties. However, the mechanisms of action VC is not known.

Objective: To establish the anticancer mechanisms of ‘bioactive fractions of VC’ on human adenocarcinoma cells.

Methods: The IC50 values of characterized VC extract and fractions in human adenocarcinoma and normal epithelial cells were determined using Sulforhodamine B (SRB) assay. Acridine Orange- Ethidium Bromide (AO-EB) assay/Hoechst 33342 assay, Comet assay, and Cell cycle analysis were used to determine apoptosis, genotoxicity, and cell cycle-specific changes in cancer cells, respectively. Rhodamine 123 (Rho-123) efflux assay and Mitoxantrone (MX) efflux assay were used to assess the inhibition of Multidrug Resistance (MDR) transporters.

Results: The dichloromethane fraction of VC (VC-DM) imparted dose-dependent cytotoxicity in human adenocarcinoma cells with fewer effects in human normal epithelial cells. This ‘sesquiterpenoids’ enriched fraction (VC-DM) induced apoptosis, DNA damage, genotoxicity, and G2/M phase arrest in human adenocarcinoma cells. Interestingly, VC-DM significantly inhibited the functional activity of MDR transporters (ABCB1 and ABCG2) and caused ‘synergistic cytotoxic effects’ with anticancer drugs in human adenocarcinoma cells.

Conclusion: The bioactivity guided fractionation of VC revealed that the specific ‘sesquiterpenoids enriched fraction’ (VC-DM) imparted cytotoxicity in human adenocarcinoma cells with fewer effects on normal cells. Mechanistic studies have shown that VC-DM induced apoptosis, DNA damage, genotoxicity, cell cycle arrest (G2/M), inhibited the functional activity of MDR transporters (ABCB1 and ABCG2), and produced ‘synergistic cytotoxic effects’ (combinatorial treatments with anticancer drugs) in human adenocarcinoma cells. Taken together, the findings of this study emphasize and validates VC-DM as a promising ‘anticancer agent’ against human adenocarcinomas, including those with a multi-drug resistant phenotype.

Keywords: Apoptosis, cytotoxicity, cell cycle arrest, dichloromethane fraction of Vernonia cinerea, genotoxicity, modulation of drug efflux transporters.

« Previous Next »
[1]
Li W, Zhang H, Assaraf YG, et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resist Updat 2016; 27: 14-29.
[http://dx.doi.org/10.1016/j.drup.2016.05.001] [PMID: 27449595]
[2]
Appadath Beeran A, Maliyakkal N, Rao CM, Udupa N. The enriched fraction of Vernonia cinerea L. induces apoptosis and inhibits multi-drug resistance transporters in human epithelial cancer cells. J Ethnopharmacol 2014; 158(Pt A): 33-42.
[http://dx.doi.org/10.1016/j.jep.2014.10.010] [PMID: 25456421]
[3]
Rawat P, Singh PK. Analysis of patents filed for the herbal therapeutics against cancer. Anticancer Plants: Properties and Application. Springer In: 2018; pp. 207-28.
[http://dx.doi.org/10.1007/978-981-10-8548-2_10]
[4]
Parolaro D, Massi P, Izzo AA, et al. Phytocannabinoids in the treatment of cancer. US20180042975, 2018.
[5]
Roura XN. Phytocannabinoids in the treatment of cancer. US20180042975, 2017.
[6]
Shetty MV. Herbal composition for the treatment and management of cancer and method of preparation thereof. US10478465, 2019.
[7]
Wangkheirakpam S. Traditional and folk medicine as a target for drug discovery. Natural Products and Drug Discovery. Elsevier In: 2018; pp. 29-56.
[http://dx.doi.org/10.1016/B978-0-08-102081-4.00002-2]
[8]
Soman GS. Process for the preparation of the CO2 extract of Azadirachta indica and herbal compositions thereof for the treatment of cancers. US20200069636, 2020.
[9]
Majolo F, Delwing LK de OB, Marmitt DJ, Bustamante-Filho IC, Goettert MI. Medicinal plants and bioactive natural compounds for cancer treatment: Important advances for drug discovery. Phytochem Lett 2019; 31: 196-207.
[http://dx.doi.org/10.1016/j.phytol.2019.04.003]
[10]
Mei BC, Lyga JW. Vernonia cinerea extracts and methods of use. US20150359732, 2015.
[11]
Segond C, Loiseau A, Petit V, Theron E. Use of vernonia extract. US9339521, 2016.
[12]
Dogra NK, Kumar S. A review on ethno-medicinal uses and pharmacology of Vernonia cinerea Less. Nat Prod Res 2015; 29(12): 1102-17.
[http://dx.doi.org/10.1080/14786419.2014.981814] [PMID: 25426778]
[13]
Segond C, Loiseau A, Petit V, Theron E. Use of veronia extract. US20170007654, 2017.
[14]
Chang LC, Turkson J, Wongwiwatthananukit S, Youn UJ, Sun D. Novel sesquiterpenoid stat3 inhibitors. US20160137663, 2016.
[15]
Kuo Y-H, Kuo Y-J, Yu A-S, et al. Two novel sesquiterpene lactones, cytotoxic vernolide-A and -B, from Vernonia cinerea. Chem Pharm Bull (Tokyo) 2003; 51(4): 425-6.
[http://dx.doi.org/10.1248/cpb.51.425] [PMID: 12672998]
[16]
Pratheeshkumar P, Kuttan G. Antimetastatic potential of vernolide-A, a sesquiterpenoid from Vernonia cinerea L. Hum Exp Toxicol 2012; 31(1): 66-80.
[http://dx.doi.org/10.1177/0960327111414279] [PMID: 21708884]
[17]
Pratheeshkumar P, Kuttan G. Effect of vernolide-A, a sesquiterpene lactone from Vernonia cinerea L., on cell-mediated immune response in B16F-10 metastatic melanoma-bearing mice. Immunopharmacol Immunotoxicol 2011; 33(3): 533-8.
[http://dx.doi.org/10.3109/08923973.2010.547501] [PMID: 21247369]
[18]
Pouyfung P, Choonate S, Wongnoppavich A, Rongnoparut P, Chairatvit K. Anti-proliferative effect of 8α-tigloyloxyhirsutinolide-13-O-acetate (8αTGH) isolated from Vernonia cinerea on oral squamous cell carcinoma through inhibition of STAT3 and STAT2 phosphorylation. Phytomedicine 2019; 52: 238-46.
[http://dx.doi.org/10.1016/j.phymed.2018.09.211] [PMID: 30599904]
[19]
Maliyakkal N, Udupa N, Pai KSR, Rangarajan A. Cytotoxic and apoptotic activities of extracts of Withania somnifera and Tinospora cordifolia in human breast cancer cells. Int J Appl Res Nat Prod 2013; 6(4): 1-10.
[20]
Zhang Z, Wang X, Huang S, et al. Apoptosis inhibitors. US20190152960, 2019.
[21]
Maliyakkal N, Appadath Beeran A, Balaji SA, Udupa N, Ranganath Pai S, Rangarajan A. Effects of Withania somnifera and Tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells: toward targeting multidrug resistance in cancer. Integr Cancer Ther 2015; 14(2): 156-71.
[http://dx.doi.org/10.1177/1534735414564423] [PMID: 25549922]
[22]
Kathawala RJ, Gupta P, Ashby CR Jr, Chen Z-S. The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist Updat 2015; 18: 1-17.
[http://dx.doi.org/10.1016/j.drup.2014.11.002] [PMID: 25554624]
[23]
Tiwari AK, Sodani K, Dai CL, Ashby CR Jr, Chen ZS. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol 2011; 12(4): 570-94.
[http://dx.doi.org/10.2174/138920111795164048] [PMID: 21118094]
[24]
Chen Z, Shi T, Zhang L, et al. Mammalian drug efflux transporters of the ATP Binding Cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett 2016; 370(1): 153-64.
[http://dx.doi.org/10.1016/j.canlet.2015.10.010] [PMID: 26499806]
[25]
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018; 18(7): 452-64.
[http://dx.doi.org/10.1038/s41568-018-0005-8] [PMID: 29643473]
[26]
Janne PA, Engelman J, Cantley LC. Methods for treating cancer resistant to ERBB therapeutics. US10322097, 2017.
[27]
Wong KW, Law YK, Efferth T, Su-Wei XU, Hamdoun S, Liu L. Treatment of subjects with multidrug-resistant cancer. US10322097, 2019.
[28]
Wong KW, Law YK, Efferth T, Kadioglu O, Liu L. Prenylated isoflavones for treatment of subjects with multidrug-resistant cancer. US9974766, 2018.
[29]
Laskin JD, Udasin R, Aleksunes L. Methods and compositions for modulating transport of a drug. US10376556, 2019.
[30]
Zhang Y-K, Wang Y-J, Gupta P, Chen Z-S. Multidrug Resistance Proteins (MRPs) and cancer therapy. AAPS J 2015; 17(4): 802-12.
[http://dx.doi.org/10.1208/s12248-015-9757-1] [PMID: 25840885]
[31]
Hongying Z. ABCG2 monoclonal antibody and uses thereof. US20190248912, 2020.
[32]
Chang C-H, Goldenberg DM. A combination of ABCG2 inhibitors with sacituzumab govitecan (immu-132) overcomes resistance to SN-38 in TROP-2 expressing cancers US20170224837A1, 2017.
[33]
Li H, Krstin S, Wink M. Modulation of multidrug resistant in cancer cells by EGCG, tannic acid and curcumin. Phytomedicine 2018; 50: 213-22.
[http://dx.doi.org/10.1016/j.phymed.2018.09.169] [PMID: 30466981]
[34]
Liao D, Zhang W, Gupta P, et al. Tetrandrine Interaction with ABCB1 reverses multidrug resistance in cancer cells through competition with anti-cancer drugs followed by downregulation of ABCB1 expression. Molecules 2019; 24(23): 4383.
[http://dx.doi.org/10.3390/molecules24234383] [PMID: 31801248]
[35]
Whittle B, Guy G, Downs D, Pate DW. Processes and apparatus for the extraction of active substances and enriched extracts from natural products. US9034395, 2015.
[36]
Stitzlein K. Quantitative HPTLC cannabinoid field testing device and method. US20200018734, 2019.
[37]
Acharya R, Sharma B, Singh R, Jain P. Phytochemical and high-performance liquid chromatography analysis of extract of Vernonia cinerea. J Drug Deliv Ther 2019; 9(1): 229-32.
[http://dx.doi.org/10.22270/jddt.v9i1.2227]
[38]
Orellana EA, Kasinski AL, Sulforhodamine B. SRB assay in cell culture to investigate cell proliferation. Bio Protoc 2016; 6(21): e1984.
[http://dx.doi.org/10.21769/BioProtoc.1984] [PMID: 28573164]
[39]
Liu K, Liu PC, Liu R, Wu X. Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry. Med Sci Monit Basic Res 2015; 21: 15-20.
[http://dx.doi.org/10.12659/MSMBR.893327] [PMID: 25664686]
[40]
Crowley LC, Marfell BJ, Waterhouse NJ. Analyzing cell death by nuclear staining with Hoechst 33342. Cold Spring Harb Protoc 2016; 9
[http://dx.doi.org/10.1101/pdb.prot087205]
[41]
Jacobberger JW, Sramkoski RM, Stefan T, Woost PG. Multiparameter cell cycle analysis. Flow Cytometry Protocols. Springer In: 2018; pp. 203-47.
[http://dx.doi.org/10.1007/978-1-4939-7346-0_11]
[42]
Schicht O. Gel electrophoresis system for single-cell gel electrophoresis. US20180095055, 2020.
[43]
Kind B, Wolf C, Engel K, Rapp A, Cardoso MC, Lee-Kirsch MA. Single-cell gel electrophoresis for the detection of genomic ribonucleotides. Genome Instability. Springer In: 2018; pp. 311-8.
[http://dx.doi.org/10.1007/978-1-4939-7306-4_21]
[44]
Sugisawa N, Ohnuma S, Ueda H, et al. Novel potent ABCB1 modulator, phenethylisoquinoline alkaloid, reverses multidrug resistance in cancer cell. Mol Pharm 2018; 15(9): 4021-30.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00457] [PMID: 30052463]
[45]
Szabodora K, Turkagnes T, Kucsmatamas H, Szakacslaszlo Homolyabalazs SV. Fluorescent dye accumulation assay. WO2019081957, 2017.
[46]
Roy A, Jauhari N, Bharadvaja N. Medicinal plants as a potential source of chemopreventive agents. Anticancer Plants: Natural Products and Biotechnological Implements. Springer In: 2018; pp. 109-39.
[http://dx.doi.org/10.1007/978-981-10-8064-7_6]
[47]
Perillo DA, Buonocore G, Balduini W. A pharmaceutical composition for the parenteral administration of melatonin, and a process for its preparation. WO2020058817, 2018.
[48]
Subramoni P, Chandrasekharan S, Madhavan J, et al. Herbal composition. US20200085904, 2020.
[49]
Abdullahi AD, Mustapha RK, Yau S, Adam MS. Exploring the Nigerian medicinal plants with anticancer activities: A pharmacological review. Mod Chem 2018; 6(2): 35-8.
[http://dx.doi.org/10.11648/j.mc.20180602.14]
[50]
Shaikh AM, Shrivastava B, Apte KG, Navale SD. Medicinal plants as a potential source of anticancer agents: A review. J Pharmacogn Phytochem 2016; 5(2): 291.
[51]
Simsek SA, Simsek S. A pharmaceutical composition with enhanced bioavailability containing a medical herbal extract. EP3581172, 2019.
[52]
Hajjar DA, Kremb S, Voolstra C, Ravasi T. Extracts of Saudi Arabian herbal plants, an anti-cancer method using such extracts, and cytological profiling using an automated high-content imaging technique. US20190298786, 2019.
[53]
Davey NS, Rustgi N, Priya P, Davey SR, Rustgi V. Herbal drug composition containing probiotic and optionally prebiotic and/or active pharmaceutical ingredient. US20170368135, 2017.
[54]
Soman G, Wargovich M. Compositions of Azadirachta indica and methods of treating cancer. WO2020047405A1, 2019.
[55]
Ledford H. US cancer institute overhauls cell lines: Veteran cells to be replaced by human tumors grown in mice. Nature 2016; 530(7591): 391-2.
[http://dx.doi.org/10.1038/nature.2016.19364] [PMID: 26911756]
[56]
Kogon BD. Phytochemical extraction systems, methods, and devices. US20190282924, 2019.
[57]
Ma L-F, Chen Y-L, Shan W-G, Zhan Z-J. Natural disesquiterpenoids: An update. Nat Prod Rep 2020; 37(7): 999-1030.
[http://dx.doi.org/10.1039/C9NP00062C] [PMID: 32104815]
[58]
Youn UJ, Wongwiwatthananukit S, Songsak T, Chang LC. Sesquiterpene lactones from Vernonia cinerea. Chem Nat Compd 2018; 54(2): 235-7.
[http://dx.doi.org/10.1007/s10600-018-2311-5]
[59]
Ren Y, Yu J, Kinghorn AD. Development of anticancer agents from plant-derived sesquiterpene lactones. Curr Med Chem 2016; 23(23): 2397-420.
[http://dx.doi.org/10.2174/0929867323666160510123255] [PMID: 27160533]
[60]
Padilla-Gonzalez GF, dos Santos FA, Da Costa FB. Sesquiterpene lactones: More than protective plant compounds with high toxicity. CRC Crit Rev Plant Sci 2016; 35(1): 18-37.
[http://dx.doi.org/10.1080/07352689.2016.1145956]
[61]
Xiang P, Guo X, Han Y-Y, Gao J-M, Tang J-J. Cytotoxic and pro-apoptotic activities of sesquiterpene lactones from Inula Britannica. Nat Prod Commun 2016; 11(1): 7-10.
[http://dx.doi.org/10.1177/1934578X1601100103]
[62]
Beeran AA, Maliyakkal N, Rao CM, Udupa N. The enriched fraction of Elephantopus scaber triggers apoptosis and inhibits multi-drug resistance transporters in human epithelial cancer cells. Pharmacogn Mag 2015; 11(42): 257-68.
[http://dx.doi.org/10.4103/0973-1296.153077] [PMID: 25829763]
[63]
Doherty J, Baehrecke EH. Life, death and autophagy. Nat Cell Biol 2018; 20(10): 1110-7.
[http://dx.doi.org/10.1038/s41556-018-0201-5] [PMID: 30224761]
[64]
Hergenrother PJ, Putt KS, Peterson QP, Valerie F. Compounds and methods for the treatment of cancer. US20190201394, 2019.
[65]
Bonacci T, Emanuele MJ. Dissenting degradation: Deubiquitinases in cell cycle and cancer. Semin Cancer Biol 2020.
[http://dx.doi.org/10.1016/j.semcancer.2020.03.008]
[66]
Zhimei DU. Methods of using cell-cycle inhibitors to modulate one or more properties of cell culture. US20180087079, 2018.
[67]
Maizels N, Le Q. Restricting nuclear protein to specific phases of the cell cycle. US20160369258, 2016.
[68]
Chen-Kiang S, Di Liberto M, Huang X. Targeting CDK4 and CDK6 in cancer therapy. US9259399, 2016.
[69]
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 2017; 17(2): 93-115.
[http://dx.doi.org/10.1038/nrc.2016.138] [PMID: 28127048]
[70]
Zhang J, Su G, Lin Y, et al. Targeting cyclin-dependent kinases in gastrointestinal cancer therapy. Discov Med 2019; 27(146): 27-36.
[PMID: 30721649]
[71]
Li Y-J, Lei Y-H, Yao N, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer 2017; 36(1): 52.
[http://dx.doi.org/10.1186/s40880-017-0219-2] [PMID: 28646911]
[72]
Bernini F, Adorni MP, Petronini PG, et al. New MDR1 inhibitors for overcoming multidrug resistance. US20170224647, 2017.
[73]
Wise JG, Vogel PD, Brewer FK, Follit CA. Inhibitors of multidrug resistance transporter P-glycoprotein. US20200138816, 2019.
[74]
Chen ZS, Shi Z, Ashby CR Jr. Use of phosphodiesterase inhibitors for treating multidrug resistance. US8673914, 2014.
[75]
Henrich CJ, Bokesch HR, Bates SE, et al. Method of inhibiting ABCG2 and related treatments. US9937217, 2018.
[76]
Breedveld P. Method for identifying modulators of BCRP/ABCG2-mediated ATP release and use of said modulators for treating diseases. EP2829880, 2015.
[77]
Özenver N, Efferth T. Integration of Phytochemicals and Phytotherapy into Cancer Precision Medicine. Approaching Complex Diseases. Springer In: 2020; pp. 355-92.
[http://dx.doi.org/10.1007/978-3-030-32857-3_16]
[78]
Kumar A, Jaitak V. Natural products as multidrug resistance modulators in cancer. Eur J Med Chem 2019; 176: 268-91.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.027] [PMID: 31103904]
[79]
Wang Y-J, Zhang Y-K, Zhang G-N, et al. Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study. Cancer Lett 2017; 396: 145-54.
[http://dx.doi.org/10.1016/j.canlet.2017.03.011] [PMID: 28302530]
[80]
Fan Y-F, Zhang W, Zeng L, et al. Dacomitinib antagonizes Multidrug Resistance (MDR) in cancer cells by inhibiting the efflux activity of ABCB1 and ABCG2 transporters. Cancer Lett 2018; 421: 186-98.
[http://dx.doi.org/10.1016/j.canlet.2018.01.021] [PMID: 29331420]
[81]
Ji N, Yang Y, Lei Z-N, et al. Ulixertinib (BVD-523) antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. Biochem Pharmacol 2018; 158: 274-85.
[http://dx.doi.org/10.1016/j.bcp.2018.10.028] [PMID: 30431011]

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