title: Anti-tumour activity of a novel coumarin-chalcone hybrid is mediated through intrinsic apoptotic pathway by inducing PUMA and altering Bax/Bcl-2 ratio.
abstract: Coumarins and chalcones are secondary plant metabolites which have shown an array of pharmacological properties including anti-tumour activity. We have previously reported on the synthesis and anti-proliferative activity of a series of novel coumarin-chalcone hybrids. Now we report on the in vivo efficacy as well as mechanism of action of the most potent molecule of the series, S009-131. Oral administration of this molecule resulted in regression of tumours induced by HeLa cell xenografts in nod SCID mice. The molecule inhibited proliferation of cervical cancer cells (HeLa and C33A) by inducing apoptosis and arresting cell cycle at G2/M phase. Apoptosis was induced through induction of caspase-dependent intrinsic pathway and alterations in the cellular levels of Bcl-2 family proteins. The mitochondrial transmembrane potential got highly depleted in S009-131 treated cells due to an increase in Bax/Bcl-2 ratio and intracellular ROS. The molecule induced release of cytochrome c into the cytosol and activation of initiator caspase-9 and executioner caspases-3/7. Tumour suppressor protein p53 and its transcriptional target PUMA were up regulated, suggesting their role in mediating the cell death. These results suggest that S009-131 is a potent candidate for the chemotherapy of cervical carcinoma.
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226 031, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.forename: Jayanta
authors.initials: J
authors.lastname: Sarkar
authors.forename: Koneni V
authors.initials: KV
authors.lastname: Sashidhara
authors.forename: Shakir
authors.initials: S
authors.lastname: Ali
authors.forename: Sudhir
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D003374:Coumarins / Q000494:pharmacology* / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D064593:Heterografts; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D047188:Chalcones; D003374:Coumarins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C000593365:ethyl 8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylate; D002599:Chalcone; D045304:Cytochromes c