T-type calcium channel antagonists, mibefradil and NNC-55-0396 inhibit cell proliferation and induce cell apoptosis in leukemia cell lines.

Abstract

BACKGROUND:

T-type Ca(2+) channels are often aberrantly expressed in different human cancers and participate in the regulation of cell cycle progression, proliferation and death.

METHODS:

RT-PCR, Q-PCR, western blotting and whole-cell patch-clamp recording were employed to assess the expression of T-type Ca(2+) channels in leukemia cell lines. The function of T-type Ca(2+) channels in leukemia cell growth and the possible mechanism of the effect of T-type Ca(2+) channel antagonists on cell proliferation and apoptosis were examined in T-lymphoma cell lines.

RESULTS:

We show that leukemia cell lines exhibited reduced cell growth when treated with T-type Ca(2+) channel inhibitors, mibefradil and NNC-55-0396 in a concentration-dependent manner. Mechanistically, these inhibitors played a dual role on cell viability: (i) blunting proliferation, through a halt in the progression to the G1-S phase; and (ii) promoting cell apoptosis, partially dependent on the endoplasmic reticulum Ca(2+) release. In addition, we observed a reduced phosphorylation of ERK1/2 in MOLT-4 cells in response to mibefradil and NNC-55-0396 treatment.

CONCLUSIONS:

These results indicate that mibefradil and NNC-55-0396 regulate proliferation and apoptosis in T-type Ca(2+) channel expressing leukemia cell lines and suggest a potential therapeutic target for leukemia.

• Authors: Weifeng Huang, Chunjing Lu, Yong Wu, Shou Ouyang, Yuanzhong Chen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 34 Pg. 54 (May 21 2015) ISSN: 1756-9966 [Electronic] England
• PMID: 25989794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Calcium Channel Blockers
• Calcium Channels, T-Type
• Cyclopropanes
• Naphthalenes
• NNC 55-0396
• Mibefradil

Topics

• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, T-Type (genetics, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclopropanes (pharmacology)
• Endoplasmic Reticulum (metabolism)
• Humans
• Leukemia (genetics, metabolism)
• Leukocytes, Mononuclear (drug effects, metabolism)
• MAP Kinase Signaling System (drug effects)
• Mibefradil (pharmacology)
• Naphthalenes (pharmacology)