Norcantharidin induced DU145 cell apoptosis through ROS-mediated mitochondrial dysfunction and energy depletion

PLoS One. 2013 Dec 19;8(12):e84610. doi: 10.1371/journal.pone.0084610. eCollection 2013.

Abstract

Norcantharidin (NCTD), a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM), the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN). Moreover, the cells could be killed in a dose-/time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen) expression, destruction of mitochondrial membrane potential (MMP), down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5'-monophosphate -activated protein kinase) . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adenosine Triphosphate / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Bisbenzimidazole
  • Blotting, Western
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Micronucleus Tests
  • Mitochondria / drug effects*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / metabolism

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Proliferating Cell Nuclear Antigen
  • Reactive Oxygen Species
  • norcantharidin
  • Adenosine Triphosphate
  • Cytochromes c
  • Superoxide Dismutase
  • AMP-Activated Protein Kinases
  • Bisbenzimidazole

Grants and funding

This study was supported the by the National Natural Science Foundation of China (No. 11105031) (http://www.nsfc.gov.cn/Portal0/default152.html) and the Youth Foundation of Fudan University of China (http://dst.fudan.edu.cn/Default.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.