title: A Novel Resveratrol Based Tubulin Inhibitor Induces Mitotic Arrest and Activates Apoptosis in Cancer Cells.
abstract: Resveratrol is one of the most widely studied bioactive plant polyphenols which possesses anticancer properties. Previously we have reported synthesis, characterization and identification of a novel resveratrol analog, SS28. In the present study, we show that SS28 induced cytotoxicity in several cancer cell lines ex vivo with an IC50value of 3-5 μM. Mechanistic evaluation of effect of SS28 in non-small cell lung cancer cell line (A549) and T-cell leukemic cell line (CEM) showed that it inhibited Tubulin polymerization during cell division to cause cell cycle arrest at G2/M phase of the cell cycle at 12-18 h time period. Immunofluorescence studies confirmed the mitotic arrest upon treatment with SS28. Besides, we show that SS28 binds to Tubulin with a dissociation constant of 0.414 ± 0.11 μM. Further, SS28 treatment resulted in loss of mitochondrial membrane potential, activation of Caspase 9 and Caspase 3, leading to PARP-1 cleavage and finally cell death via intrinsic pathway of apoptosis. Importantly, treatment with SS28 resulted in regression of tumor in mice. Hence, our study reveals the antiproliferative activity of SS28 by disrupting microtubule dynamics by binding to its cellular target Tubulin and its potential to be developed as an anticancer molecule.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Institute of Bioinformatics and Applied Biotechnology, Electronic City, Bangalore 560 100, India.
authors.forename: Vidya
authors.initials: V
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Hegde
authors.affiliation: Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560 010, India.
authors.forename: Sujeet
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560 010, India.
authors.forename: Subhas S
authors.initials: SS
authors.lastname: Karki
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
authors.affiliation: Institute of Bioinformatics and Applied Biotechnology, Electronic City, Bangalore 560 100, India.
authors.forename: Bibha
authors.initials: B
authors.lastname: Choudhary
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C000627763:(E)-1,2,3-trimethoxy-5-(4-methylstyryl)benzene (6h); D000972:Antineoplastic Agents, Phytogenic; D001555:Benzene Derivatives; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; D000077185:Resveratrol