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

Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 02/2012; 11(4):898-908. DOI: 10.1158/1535-7163.MCT-11-0860
Source: PubMed


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.

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Available from: Vincent Njar, Dec 26, 2015
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    • "cells (human glioblastoma) The combination of CQ and ZD6474 (tyrosine kinase inhibitor) shows a significant advantage over CQ or ZD6474 alone in reducing tumor growth.[38]U87MG cells (human glioblastoma) The combination of CQ and bevacizumab (VEGF-neutralizing antibody) shows a significant advantage over bevacizumab alone in reducing tumor growth.[39]SKBR-3 cells (mammary carcinoma) Potentiate chemotherapy using VN/12-1 (a bile acid metabolism blocking agent) in reducing tumor growth.[40]PC-3 "
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    ABSTRACT: Autophagy is a catabolic degradation process in which cellular proteins and organelles are engulfed by double-membrane autophagosomes and degraded in lysosomes. Autophagy has emerged as a critical pathway in tumor development and cancer therapy, although its precise function remains a conundrum. The current consensus is that autophagy has a dual role in cancer. On the one hand, autophagy functions as a tumor suppressor mechanism by preventing the accumulation of damaged organelles and aggregated proteins. On the other hand, autophagy is a key cell survival mechanism for established tumors; therefore autophagy inhibition suppresses tumor progression. Here, we summarize recent progress on the role of autophagy in tumorigenesis and cancer therapy.
    Full-text · Article · Feb 2015 · F1000 Prime Reports
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    • "With regard to a number of other agents of varying mechanisms of action, enhanced effectiveness of a Src family kinase inhibitor was observed when combined with chloroquine in a xenograft model of prostate cancer (Wu et al., 2010), to interleukin-2 in a model of murine colorectal carcinoma (Liang et al., 2012), and to bevacizumab in glioblastoma (Hu et al., 2012); the latter two findings are of particular interest and relevance and will be addressed in more detail below. Conversely, only quite modest improvement in response to chemotherapeutic agents was detected for chloroquine in combination with an mTOR inhibitor in MCF-7 xenografts (Loehberg et al., 2012), with voranistat in colon carcinoma (Carew et al., 2010), with perifosine in lung cancer xenografts (Fu et al., 2009), with a dual phosphatidylinositide 3-kinase/ protein kinase B/mTOR inhibitor in non-small cell lung cancer xenografts (Xu et al., 2011), with a retinoic acid metabolism blocker in breast tumor cells (Godbole et al., 2012), and with panobinostat in breast cancer (Rao et al., 2012); in the latter studies, the lack of impact could be ascribed to the use of an unusually low dose of chloroquine of 10 mg/kg, which was apparently necessitated by the high degree of toxicity that was observed with chloroquine alone in this work. A particularly relevant issue is that it is frequently unclear whether chloroquine has achieved levels in the tumor cells that are likely to be therapeutically effective in inhibiting autophagy . "
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    ABSTRACT: Recognition of the cytoprotective functions of autophagy that occur in tumor cells exposed to various forms of chemotherapy or radiation has generated intense interest in the possibility that pharmacological interference with autophagy could provide a clinical strategy for overcoming therapeutic resistance. Multiple clinical trials are currently in progress to evaluate the antimalarial agent chloroquine (generally in its clinical formulation as hydroxychloroquine) and its impact on various forms of cancer therapy. In this commentary/review, we focus on the relatively limited number of studies in the literature where chloroquine has been tested in combination with chemotherapy or radiation in experimental tumor-bearing animal models. We also present recent data from our own laboratories, in cell culture experiments as well as in vivo studies, which demonstrate that neither chloroquine nor silencing of an autophagy regulatory gene was effective in conferring radiation sensitivity in an experimental model of breast cancer. The capacity for sensitization by chloroquine appears to be quite wide-ranging, with dramatic effects for some drugs/tumor models and modest or minimal effects in others. One possible caveat is that with only a few exceptions, experiments have generally been performed in xenograft models, thereby eliminating the involvement of the immune system, which might ultimately prove to play a central role in determining the effectiveness of autophagy inhibition in chemosensitization or radiosensitization. Nevertheless, a careful review of the current literature suggests that caution is likely to be warranted in translating preclinical findings relating to autophagy inhibition as an adjunctive therapeutic strategy.
    Full-text · Article · Jan 2013 · Journal of Pharmacology and Experimental Therapeutics

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