title: Shikonin selectively induces apoptosis in human prostate cancer cells through the endoplasmic reticulum stress and mitochondrial apoptotic pathway.
abstract: BACKGROUND
  Despite the recent progress in screening and therapy, a majority of prostate cancer cases eventually attain hormone refractory and chemo-resistant attributes. Conventional chemotherapeutic strategies are effective at very high doses for only palliative management of these prostate cancers. Therefore chemo-sensitization of prostate cancer cells could be a promising strategy for increasing efficacy of the conventional chemotherapeutic agents in prostate cancer patients. Recent studies have indicated that the chemo-preventive natural agents restore the pro-apoptotic protein expression and induce endoplasmic reticulum stress (ER stress) leading to the inhibition of cellular proliferation and activation of the mitochondrial apoptosis in prostate cancer cells. Therefore reprogramming ER stress-mitochondrial dependent apoptosis could be a potential approach for management of hormone refractory chemoresistant prostate cancers. We aimed to study the effects of the natural naphthoquinone Shikonin in human prostate cancer cells.
  
  
  RESULTS
  The results indicated that Shikonin induces apoptosis in prostate cancer cells through the dual induction of the endoplasmic reticulum stress and mitochondrial dysfunction. Shikonin induced ROS generation and activated ER stress and calpain activity. Moreover, addition of antioxidants attenuated these effects. Shikonin also induced the mitochondrial apoptotic pathway mediated through the enhanced expression of the pro-apoptotic Bax and inhibition of Bcl-2, disruption of the mitochondrial membrane potential (MMP) followed by the activation of caspase-9, caspase-3, and PARP cleavage.
  
  
  CONCLUSIONS
  The results suggest that shikonin could be useful in the therapeutic management of hormone refractory prostate cancers due to its modulation of the pro-apoptotic ER stress and mitochondrial apoptotic pathways.
authors: Cell Death Research Laboratory, Endocrinology Division CSIR-Central Drug Research Institute, Lucknow, 226031, India. rgara@uthsc.edu.|Center for Cancer Research, UTHSC, Memphis, TN, USA. rgara@uthsc.edu.
authors: Rishi Kumar
authors: RK
authors: Gara
authors: Department of Radiotherapy, King George Medical University, Lucknow, 226003, India. vikaskgmu@gmail.com.
authors: Vikas Kumar
authors: VK
authors: Srivastava
authors: Department of Radiotherapy, King George Medical University, Lucknow, 226003, India. shivalivi@gmail.com.
authors: Shivali
authors: S
authors: Duggal
authors: Cell Death Research Laboratory, Endocrinology Division CSIR-Central Drug Research Institute, Lucknow, 226031, India. jaspreet.cdri@gmail.com.
authors: Jaspreet Kaur
authors: JK
authors: Bagga
authors: Department of Radiotherapy, King George Medical University, Lucknow, 226003, India. drmlbhatt@yahoo.com.
authors: Mlb
authors: M
authors: Bhatt
authors: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India. s_sanyal@cdri.res.in.
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Cell Death Research Laboratory, Endocrinology Division CSIR-Central Drug Research Institute, Lucknow, 226031, India. dpm@cdri.res.in.
authors: Durga Prasad
authors: DP
authors: Mishra
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009285:Naphthoquinones / Q000494:pharmacology*; D011471:Prostatic Neoplasms
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; C016101:shikonin