Purushottamachar Puranik - Autophagy Inhibition Synergistically Enhances Anticancer Efficacy of RAMBA, VN/12-1 in SKBR-3 Cells, and Tumor Xenografts.

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      Publication Details (including relevant citation   information):

      Mol Cancer   Ther. 2012 Apr;11(4):898-908. Epub 2012 Feb 14.

      Abstract:

      VN/12-1 is a novel retinoic acid metabolism blocking agent   discovered in our laboratory. The purpose of the study was to   elucidate the molecular mechanism of anticancer activity of   VN/12-1 in breast cancer cell lines and in tumor xenografts. We   investigated the effects of VN/12-1 on induction of autophagy and   apoptosis in SKBR-3 cells. Furthermore, we also examined the   impact of pharmacologic and genomic inhibition of autophagy on   anticancer activity of VN/12-1. Finally, the antitumor activity   of VN/12-1 was evaluated as a single agent and in combination   with autophagy inhibitor chloroquine in an SKBR-3 mouse xenograft   model. Short exposure of low dose (<10 μmol/L) of VN/12-1   induced endoplasmic reticulum stress, autophagy, and inhibited   G(1)-S phase transition and caused a protective response.   However, a higher dose of VN/12-1 initiated apoptosis in vitro.   Inhibition of autophagy using either pharmacologic inhibitors or   RNA interference of Beclin-1 enhanced anticancer activity induced   by VN/12-1 in SKBR-3 cells by triggering apoptosis. Importantly,   VN/12-1 (5 mg/kg twice weekly) and the combination of VN/12-1 (5   mg/kg twice weekly) + chloroquine (50 mg/kg twice weekly)   significantly suppressed established SKBR-3 tumor growth by 81.4%   (P < 0.001 vs. control) and 96.2% (P < 0.001 vs. control),   respectively. Our novel findings suggest that VN/12-1 may be   useful as a single agent or in combination with autophagy   inhibitors for treating human breast cancers. Our data provides a   strong rationale for clinical evaluation of VN/12-1 as single   agent or in combination with autophagy inhibitors.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/22334589