Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription.

Abstract

Involvement of activities of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) remains unsolved in norcantharidin-associated breast cancer cell apoptosis. This study investigated the anti-cancer effect of norcantharidin and its underlying mechanism in two human breast cancer cell lines, estrogen receptor (ER)- HS-578T and ER+ MCF-7 cells. Norcantharidin induced potent cytotoxicity and arrested cell growth through increasing phosphorylation of Chk1, Chk2 and total p21(Waf1/Cip1) and reducing cyclin B and cdc25c expression. It also induced apoptosis through extrinsic death receptor and intrinsic mitochondrial pathways by cytochrome c release, caspase activation, oligonucleosome appearance, PARP cleavage, and aberration of Bcl-2 family protein expression and phosphorylation. Although norcantharidin did not affect STAT1, STAT3, and STAT5 protein expression, it suppressed STAT3 and STAT5 phosphorylation in HS-578T cells, whereas it up-regulated STAT1 phosphorylation and down-regulated STAT5 phosphorylation in MCF-7 cells. Moreover, norcantharidin activated MAPK family member proteins, extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK), were all phosphorylated by treatment. Pretreatment with selective kinase inhibitors significantly attenuated the norcantharidin-induced cytotoxicity in breast cancer cells. These findings suggest the potential involvement of MAPK and STAT pathways in norcantharidin-induced apoptogenesis. Norcantharidin may be an effective anti-cancer drug against breast cancer.

• Authors: Pei-Yu Yang, Ming-Feng Chen, Ying-Hsien Kao, Dan-Ning Hu, Fang-Rong Chang, Yang-Chang Wu
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 25 Issue 3 Pg. 699-707 (Apr 2011) ISSN: 1879-3177 [Electronic] England
• PMID: 21266192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• STAT Transcription Factors
• norcantharidin
• Cytochromes c
• Mitogen-Activated Protein Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytochromes c (metabolism)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• STAT Transcription Factors (metabolism)