"Desenvolvimento e progressão de tumores da mama: onde o Ca2+ se encontra com o AMPc."

Abstract

With great epidemiological importance worldwide, breast cancer is considered the most common and the one with the highest mortality among women. Important for control of intracellular Ca2+ concentration and already used as a pharmacological target in treatment of several diseases, voltage-gated Ca2+ channels expression has been associated with tumor development and regulation of several cellular processes, such as proliferation, migration, cell cycle and apoptosis. In this sense, repositioning of some drugs that block these channels has been investigated for a more effective, specific cancer treatment and with fewer side effects. Among these, we can mention verapamil and nifedipine, antihypertensive drugs extremely used in clinical medicine, but has controversial data regarding their effects on tumor development. Thus, this study seeks to understand whether there is a relationship between the use of Ca2+ blockers, verapamil and nifedipine, and the risk of developing breast cancer, seeking to identify the mechanism of action behind this association, focusing on Ca2+/cAMP-dependent signaling pathways. Our results demonstrate that prolonged use of verapamil and nifedipine was able to increase cell proliferation, mainly in non-tumor breast cells. The prolonged use of these blockers altered Ca2+ intracellular concentration, as well as the expression of proteins such as NFκB and EPAC. Furthermore, 100 μM verapamil administration in non-tumor cells increased not only the cAMP intracellular concentration, but also the PKA activity, demonstrating that there is an association between the signaling pathways controlled by Ca2+ and cAMP in the mechanism of action activated by this drug. Thus, this study demonstrated for the first time that in vitro studies indicate the presence of a relationship between prolonged use of CCB and the increased proliferative capacity of non-tumor breast cells, which may be a risk factor for breast cancer development. Not only, we emphasize that BCC prescription for cardiac arrhythmias and hypertension treatment in women with a family history of neoplasms should be carefully analyzed and further studies that seek to unravel the association between Ca2+ and cAMP signaling pathways as a mechanism of action should be conducted.