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Inhibition of tumor cell invasion by verapamil
K H Yohem1, J L Clothier, S L Montague
1Department of Anatomy, College of Medicine, University of Arizona, Tucson 85724.
Abstract:
Verapamil, a calcium channel antagonist, inhibits murine B16 melanoma and colon adenocarcinoma C26 tumor metastasis by altering platelet aggregation [Tsuruo, T., et al. (1985) Cancer Chemother. Pharmacol., 14:30-33]. However, the role of calcium homeostasis in regulating several biochemical pathways implicated in other steps of the metastatic cascade suggests that calcium channel antagonists could also inhibit metastasis by other mechanisms. In this report, non-toxic doses of verapamil reversibly decreased human A375M and C8161 melanoma cell invasion and metastasis in a dose-dependent manner. Verapamil reduced cellular invasion and metastases by up to 96% (range 78-96%). Concomitantly, verapamil disrupts microtubule and microfilament organization and inhibits unidirectional cell migration but does not affect cellular adhesion to endothelial monolayers or reconstituted basement membranes. In addition, tumor cells treated with verapamil have a decrease in mRNA of type IV collagenase, a proteinase important in tumor cell degradation of basement membranes. Collectively, these data offer additional evidence regarding the mechanisms of action of verapamil as an anti-metastatic agent.
Insights
Verapamil, a calcium channel blocker, significantly reduces melanoma cell invasion and metastasis. This drug impacts cell migration and degrades key proteins involved in tumor spread.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Verapamil, a calcium channel antagonist, previously demonstrated inhibition of tumor metastasis in murine models.
- The broader role of calcium homeostasis in metastatic pathways suggests potential for calcium channel antagonists beyond platelet aggregation.
- Investigating alternative mechanisms of verapamil's anti-metastatic effects is crucial for understanding its therapeutic potential.
Purpose of the Study:
- To investigate the effects of non-toxic verapamil doses on human melanoma cell invasion and metastasis.
- To elucidate the specific cellular and molecular mechanisms by which verapamil inhibits metastasis.
Main Methods:
- Treatment of human melanoma cell lines (A375M and C8161) with varying doses of verapamil.
- Assessment of cellular invasion, metastasis, cell migration, and adhesion.
- Analysis of microtubule and microfilament organization.
- Quantification of type IV collagenase mRNA levels in treated tumor cells.
Main Results:
- Verapamil significantly reduced human melanoma cell invasion and metastasis in a dose-dependent manner (up to 96% reduction).
- Verapamil disrupted microtubule and microfilament organization, inhibiting unidirectional cell migration.
- Verapamil treatment led to decreased mRNA levels of type IV collagenase, a key enzyme in basement membrane degradation.
Conclusions:
- Verapamil exhibits potent anti-metastatic activity against human melanoma cells through mechanisms beyond platelet aggregation.
- Verapamil's effects on cytoskeletal organization and matrix metalloproteinase expression contribute to its anti-metastatic properties.
- These findings provide further evidence for verapamil's potential as an anti-metastatic agent targeting multiple steps in the metastatic cascade.