Autophagy inhibition synergistically enhances anticancer efficacy of RAMBA, VN/12-1 in SKBR-3 cells, and tumor xenografts.

Molecular Cancer Therapeutics
Abhijit M GodboleVincent C O Njar

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 b...Continue Reading

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Citations

May 15, 2012·Cancer Chemotherapy and Pharmacology·Abhijit M GodboleVincent C O Njar
Jan 8, 2013·The Journal of Pharmacology and Experimental Therapeutics·Molly L BristolDavid A Gewirtz
Jul 24, 2012·Biochemical and Biophysical Research Communications·Ramesh R Kaini, Chien-An A Hu
Apr 22, 2015·Cancer Letters·Juanjuan TangJunnian Zheng
May 4, 2017·Biological Reviews of the Cambridge Philosophical Society·Juan LorenteMatilde E LLeonart

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