Cardiovascular diseases and neoplastic diseases are the leading causes of death worldwide. These illnesses often co-exist, deteriorate the body condition, and complicate the therapies. In this context, we analyzed the potential oncological role of cardiovascular-antihypertensive drugs (AHD) on extravasating cancer cells through endothelial cells. AHDs have been studied to influence vascular remodeling and cancer cell migration, and several studies indicated both cancer promotive and protective activity. Among various AHDs, Calcium channel blockers (CCBs) have been clinically prescribed for more than two decades, and almost 49.8% of hypertension patients are prescribed with CCBs in India. It is known that calcium ions play an essential role in many functions such as cell migration, cellular traction, apoptosis, and hence even a minor antagonists action of CCBs can affect major physiological events. While most CCBs target vascular smooth muscle cells, CCBs have been studied to affect both endothelial cells and cancer cells and thus participate in neoplastic diseases. Therefore, studying the concurrent effect of these CCBs on cancer cells becomes important in managing cancer effectively.
Here, we report the influence of conventional CCBs—Verapamil Hydrochloride and Nifedipine-on kinetics of cell spreading, migration, and transmigration of cancer cells (MCF-7 and MDA-MB-231) through endothelial cell monolayers (HUVEC), in both co-culture and mono-culture systems using light microscopy and trans-endothelial impedance measurements. We further examined the role of the actin–cytoskeleton in regulating CCB-mediated trans-migration and tested whether the treatment with CCBs regulates key extravasation-regulating factors such as cellular traction and mechanics of the plasma membrane.
Our results show that the presence of Nifedipine increases the average cell area, distance migrated, and extravasation-frequency of MCF-7 cells through the HUVEC monolayer. In contrast, Verapamil has the opposite effect on morphology and extravasation. Our results from the transmigration of cancer cells through endothelial cells showed that Nifedipine treatment enhanced the attachment of MCF-7 cells and compromised the HUVEC’s barrier property, while Verapamil had the opposite effect. Fluorescence staining of junctional protein (VE-Cadherin) also confirmed a loss in cell-cell integrity post-Nifedipine treatment. Our traction stress data showed that both Nifedipine and Verapamil decreased the mean traction stress in MCF-7 and HUVEC. Results from the membrane-deformation analysis show that while Nifedipine increased membrane-deformation in both the cell types, Verapamil did not affect MCF-7 and decreased the deformation in HUVEC. From our results, we postulate that Nifedipine decreases the membrane stiffness and helps the cancer cells extravasate through the endothelial cell by accelerating the migration and elongating the cells. Verapamil, on the contrary, makes the cell stiffer, decelerates migration, and decreases extravasation frequency. Our study on the influence of CCBs on the mechanics of cancer cells was also consistent with similar molecular biology studies, and a judicious choice of CCB is essential in managing co-therapy of cancer and hypertension.