Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma
Identifieur interne : 000937 ( Main/Exploration ); précédent : 000936; suivant : 000938Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma
Auteurs : Sumit Siddharth ; Nethaji Muniraj ; Neeraj K. Saxena ; Dipali SharmaSource :
- Cancers [ 2072-6694 ] ; 2019.
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
Url:
DOI: 10.3390/cancers11040453
PubMed: 30934990
PubMed Central: 6521104
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma</title>
<author><name sortKey="Siddharth, Sumit" sort="Siddharth, Sumit" uniqKey="Siddharth S" first="Sumit" last="Siddharth">Sumit Siddharth</name>
<affiliation><nlm:aff id="af1-cancers-11-00453">Department of Oncology, School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA;<email>ssiddha2@jhmi.edu</email>
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<author><name sortKey="Muniraj, Nethaji" sort="Muniraj, Nethaji" uniqKey="Muniraj N" first="Nethaji" last="Muniraj">Nethaji Muniraj</name>
<affiliation><nlm:aff id="af1-cancers-11-00453">Department of Oncology, School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA;<email>ssiddha2@jhmi.edu</email>
(S.S.);<email>nmunira1@jhmi.edu</email>
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<author><name sortKey="Saxena, Neeraj K" sort="Saxena, Neeraj K" uniqKey="Saxena N" first="Neeraj K." last="Saxena">Neeraj K. Saxena</name>
<affiliation><nlm:aff id="af2-cancers-11-00453">Early Detection Research Group, 22 National Cancer Institute, Rockville, MD 20892, USA;<email>neeraj.saxena@nih.gov</email>
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<author><name sortKey="Sharma, Dipali" sort="Sharma, Dipali" uniqKey="Sharma D" first="Dipali" last="Sharma">Dipali Sharma</name>
<affiliation><nlm:aff id="af1-cancers-11-00453">Department of Oncology, School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA;<email>ssiddha2@jhmi.edu</email>
(S.S.);<email>nmunira1@jhmi.edu</email>
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<series><title level="j">Cancers</title>
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<front><div type="abstract" xml:lang="en"><p>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 <italic>Withania somnifera</italic>
, 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. </p>
</div>
</front>
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<name sortKey="Saxena, Neeraj K" sort="Saxena, Neeraj K" uniqKey="Saxena N" first="Neeraj K." last="Saxena">Neeraj K. Saxena</name>
<name sortKey="Sharma, Dipali" sort="Sharma, Dipali" uniqKey="Sharma D" first="Dipali" last="Sharma">Dipali Sharma</name>
<name sortKey="Siddharth, Sumit" sort="Siddharth, Sumit" uniqKey="Siddharth S" first="Sumit" last="Siddharth">Sumit Siddharth</name>
</noCountry>
</tree>
</affiliations>
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