Decrypting the Molecular Mechanistic Pathways Delineating the Chemotherapeutic Potential of Ruthenium-Phloretin Complex in Colon Carcinoma Correlated with the Oxidative Status and Increased Apoptotic Events

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2020 Jun 23

PMID 32566099

Citations 7

Authors

Guoguo Jin

Zhenjiang Zhao

Tania Chakraborty

Aikyadeep Mandal

Arka Roy

Souvik Roy

Zhiping Guo

Affiliations

Soon will be listed here.

Abstract

To explore fresh strategies in colorectal cancer (CRC) chemotherapy, we evaluated the capability of the ruthenium-phloretin complex in exterminating colon cancer by effectively addressing multiple apoptotic mechanisms on HT-29 cancer cells together with an animal model of colorectal cancer activated by 1,2-dimethylhydrazine and dextran sulfate sodium. Our current approach offers tangible evidence of the application of the ruthenium-phloretin complex in future chemotherapy. The complex triggers intrinsic apoptosis triggered by p53 and modulates the Akt/mTOR pathway along with other inflammatory biomarkers. The ruthenium-phloretin complex has been synthesized and successfully characterized by numerous spectroscopic methodologies accompanied by DPPH, FRAP, and ABTS assays assessing its antioxidant potential. Studies conducted in human cell lines revealed that the complex improved levels of p53 and caspase-3 while diminishing the activities of VEGF and mTOR, triggers apoptosis, and induces fragmentation of DNA in the HT-29 cells. Toxicity studies were conducted to identify the therapeutic doses of the novel complex in animal models. The outcomes of the in vivo report suggest that the complex was beneficial in repressing multiplicity of aberrant crypt foci as well as hyperplastic lesions and also promoted increased levels of CAT, SOD, and glutathione. In addition, the ruthenium-phloretin complex was able to control cell proliferation and boosted apoptotic outbursts in cancer cells associated with the increase in cellular response towards Bax while diminishing responses towards Bcl-2, NF-B, and MMP-9. Our observations from the experiments deliver testament that the ruthenium-phloretin complex has the potential to act as a promising chemotherapeutic agent in colorectal cancer because it can affect the growth of ACF and hyperplastic abrasions in the colon tissues by evoking cell death.

Citing Articles

Chalcones and Gastrointestinal Cancers: Experimental Evidence.

Michalkova R, Kello M, cizmarikova M, Bardelcikova A, Mirossay L, Mojzis J Int J Mol Sci. 2023; 24(6).

PMID: 36983038 PMC: 10059739. DOI: 10.3390/ijms24065964.

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Ribeiro N, Farinha P, Pinho J, Luiz H, Meszaros J, Galvao A Pharmaceutics. 2022; 14(12).

PMID: 36559078 PMC: 9785144. DOI: 10.3390/pharmaceutics14122583.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions.

Tuli H, Rath P, Chauhan A, Ramniwas S, Vashishth K, Varol M Molecules. 2022; 27(24).

PMID: 36557950 PMC: 9787340. DOI: 10.3390/molecules27248819.

Metallophenolomics: A Novel Integrated Approach to Study Complexation of Plant Phenolics with Metal/Metalloid Ions.

Fedenko V, Landi M, Shemet S Int J Mol Sci. 2022; 23(19).

PMID: 36232672 PMC: 9570091. DOI: 10.3390/ijms231911370.

KIFC3 Promotes Proliferation, Migration, and Invasion in Colorectal Cancer PI3K/AKT/mTOR Signaling Pathway.

Liao H, Zhang L, Lu S, Li W, Dong W Front Genet. 2022; 13:848926.

PMID: 35812733 PMC: 9257096. DOI: 10.3389/fgene.2022.848926.

References

Fujioka T, KASHIWADA Y, Kilkuskie R, Cosentino L, Ballas L, Jiang J . Anti-AIDS agents, 11. Betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids. J Nat Prod. 1994; 57(2):243-7. DOI: 10.1021/np50104a008. View

Ma L, Wang R, Nan Y, Li W, Wang Q, Jin F . Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases. Int J Oncol. 2015; 48(2):843-53. DOI: 10.3892/ijo.2015.3304. View

Patil P, Saklani A, Gambhire P, Mehta S, Engineer R, DeSouza A . Colorectal Cancer in India: An Audit from a Tertiary Center in a Low Prevalence Area. Indian J Surg Oncol. 2017; 8(4):484-490. PMC: 5705504. DOI: 10.1007/s13193-017-0655-0. View

Rosse T, Olivier R, Monney L, Rager M, Conus S, Fellay I . Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature. 1998; 391(6666):496-9. DOI: 10.1038/35160. View

Pathy S, Lambert R, Sauvaget C, Sankaranarayanan R . The incidence and survival rates of colorectal cancer in India remain low compared with rising rates in East Asia. Dis Colon Rectum. 2012; 55(8):900-6. DOI: 10.1097/DCR.0b013e31825afc4e. View

Platz E, Willett W, Colditz G, Rimm E, Spiegelman D, Giovannucci E . Proportion of colon cancer risk that might be preventable in a cohort of middle-aged US men. Cancer Causes Control. 2000; 11(7):579-88. DOI: 10.1023/a:1008999232442. View

de Kok T, Van Breda S, Manson M . Mechanisms of combined action of different chemopreventive dietary compounds: a review. Eur J Nutr. 2008; 47 Suppl 2:51-9. DOI: 10.1007/s00394-008-2006-y. View

Giorgio M, Trinei M, Migliaccio E, Pelicci P . Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?. Nat Rev Mol Cell Biol. 2007; 8(9):722-8. DOI: 10.1038/nrm2240. View

Hubin T, Amoyaw P, Roewe K, Simpson N, Maples R, Freeman T . Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands. Bioorg Med Chem. 2014; 22(13):3239-44. PMC: 4119818. DOI: 10.1016/j.bmc.2014.05.003. View

10.

Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B . The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017; 7(3):339-348. PMC: 5651054. DOI: 10.15171/apb.2017.041. View

11.

Awasthi N, Yen P, Schwarz M, Schwarz R . The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J Cell Biochem. 2011; 113(3):784-91. DOI: 10.1002/jcb.23405. View

12.

Karthik Kumar V, Vennila S, Nalini N . Modifying effects of morin on the development of aberrant crypt foci and bacterial enzymes in experimental colon cancer. Food Chem Toxicol. 2008; 47(2):309-15. DOI: 10.1016/j.fct.2008.11.017. View

13.

Liu X, Wu J, Zhang D, Wang K, Duan X, Zhang X . A Network Pharmacology Approach to Uncover the Multiple Mechanisms of Willd. on Colorectal Cancer. Evid Based Complement Alternat Med. 2018; 2018:6517034. PMC: 5829364. DOI: 10.1155/2018/6517034. View

14.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

15.

Johnson S, Gulhati P, Rampy B, Han Y, Rychahou P, Doan H . Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010; 210(5):767-76, 776-8. PMC: 2895913. DOI: 10.1016/j.jamcollsurg.2009.12.008. View

16.

Benzie I, Strain J . The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem. 1996; 239(1):70-6. DOI: 10.1006/abio.1996.0292. View

17.

Xia Y, Shen S, Verma I . NF-κB, an active player in human cancers. Cancer Immunol Res. 2014; 2(9):823-30. PMC: 4155602. DOI: 10.1158/2326-6066.CIR-14-0112. View

18.

Khan M, Chen H, Wan X, Tania M, Xu A, Chen F . Regulatory effects of resveratrol on antioxidant enzymes: a mechanism of growth inhibition and apoptosis induction in cancer cells. Mol Cells. 2013; 35(3):219-25. PMC: 3887918. DOI: 10.1007/s10059-013-2259-z. View

19.

Glienke W, Maute L, Wicht J, Bergmann L . The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines. Tumour Biol. 2011; 33(3):757-65. DOI: 10.1007/s13277-011-0290-2. View

20.

Cao W, Zheng W, Chen T . Ruthenium polypyridyl complex inhibits growth and metastasis of breast cancer cells by suppressing FAK signaling with enhancement of TRAIL-induced apoptosis. Sci Rep. 2015; 5:9157. PMC: 4361883. DOI: 10.1038/srep09157. View