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Cancers 2019, 11(4), 453; https://doi.org/10.3390/cancers11040453

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma

1
Department of Oncology, School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA
2
Early Detection Research Group, 22 National Cancer Institute, Rockville, MD 20892, USA
*
Author to whom correspondence should be addressed.
Received: 12 March 2019 / Revised: 21 March 2019 / Accepted: 26 March 2019 / Published: 30 March 2019
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Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality, and despite recent advances in early diagnosis and therapeutics, HCC related morbidity and mortality rate continue to rise. Clearly, it is imperative to develop novel effective therapies for HCC to improve long-term survival of HCC patients. We found that Withaferin A (WFA), a bioactive compound derived from Withania somnifera, is an effective agent for HCC inhibition. Interestingly, we observed that in addition to inducing apoptotic cell death, WFA also induces autophagy in HCC cells. Utilizing mRFP-EGFP-LC3B, LC3B-GFP/Lysotracker and LC3B-GFP/Rab7-RFP, we show that WFA induces autophagosomes-lysosomes fusion. WFA-induced autolysosomes exhibit intact protein degradation activity as evident with cathepsin-D activation and DQ-BSA assays. Importantly, we present that inhibiting WFA-induced autophagy either by blocking autophagosome-formation or by elevating lysosomal pH (Chloroquine and Bafilomycin) enhances WFA-induced growth-inhibition and apoptosis, indicating the presence of cytoprotective autophagy. Indeed, WFA and CQ combination shows synergism and higher efficacy in comparison to either monotherapy. Collectively, we reveal that the efficacy of WFA is somewhat diminished by the concomitant induction of cytoprotective autophagy which can be successfully conquered by cotreatment with CQ, and we pave the way for development of a novel combination therapeutic strategy for HCC. View Full-Text
Keywords: hepatocellular carcinoma; LC3B; cytoprotective autophagy; cathepsin-D; withaferin A hepatocellular carcinoma; LC3B; cytoprotective autophagy; cathepsin-D; withaferin A
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Siddharth, S.; Muniraj, N.; Saxena, N.K.; Sharma, D. Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma. Cancers 2019, 11, 453.

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