title: Role of metabolic modulator Bet-CA in altering mitochondrial hyperpolarization to suppress cancer associated angiogenesis and metastasis.
abstract: Solid tumors characteristically reflect a metabolic switching from glucose oxidation to glycolysis that plays a fundamental role in angiogenesis and metastasis to facilitate aggressive tumor outcomes. Hyperpolarized mitochondrial membrane potential is a manifestation of malignant cells that compromise the intrinsic pathways of apoptosis and confer a suitable niche to promote the cancer associated hallmark traits. We have previously reported that co-drug Bet-CA selectively targets cancer cells by inducing metabolic catastrophe without a manifest in toxicity. Here we report that the same molecule at a relatively lower concentration deregulates the cardinal phenotypes associated with angiogenesis and metastasis. In mice syngeneic 4T1 breast cancer model, Bet-CA exhibited effective abrogation of angiogenesis and concomitantly obliterated lung metastasis consistent with altered mitochondrial bioenergetics. Furthermore, Bet-CA significantly lowered vascular endothelial growth factor (VEGF) levels and obviated matrix metalloproteases (MMP-2/9) production directly to the criterion where abrogation of autocrine VEGF/VEGFR2 signalling loop was documented. In vitro studies anticipatedly documented the role of Bet-CA in inhibiting actin remodeling, lamellipodia formation and cell membrane ruffling to constitutively suppress cell motility and invasion. Results comprehensively postulate that Bet-CA, a mitochondria targeting metabolic modulator may serve as an excellent candidate for combating angiogenesis and metastasis.
authors.affiliation: Drug Development Diagnostic and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Suchandrima
authors.initials: S
authors.lastname: Saha
authors.affiliation: Drug Development Diagnostic and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Monisankar
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Drug Development Diagnostic and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Samir Kumar
authors.initials: SK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000601985:Bet-CA compound; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse