Valproic acid inhibits cell growth in both MCF-7 and MDA-MB231 cells by triggering different responses in a cell type-specific manner

Abstract

Background Breast cancer is the second leading cause of death among women after lung cancer. Despite the improvement in prevention and in therapy, breast cancer still remains a threat, both for pre- and postmenopausal women, due to the development of drug resistance. To counteract that, novel agents regulating gene expression have been studied in both hematologic and solid tumors. The Histone Deacetylase (HDAC) inhibitor Valproic Acid (VA), used for epilepsy and other neuropsychiatric diseases, has been demonstrated a strong antitumoral and cytostatic activity. In this study, we tested the effects of Valproic Acid on the signaling pathways involved in breast cancer cells viability, apoptosis and in Reactive Oxygen Species (ROS) production using ER-α positive MCF-7 and triple negative MDA-MB-231 cells. Methods Cell proliferation assay was performed by MTT Cell cycle, ROS levels and apoptosis were analyzed by flow cytometry, protein levels were detected by Western Blotting. Results Cell treatment with Valproic Acid reduced cell proliferation and induced G0/G1 cell cycle arrest in MCF-7 and G2/M block in MDA-MB-231 cells. In addition, in both cells the drug enhanced the generation of ROS by the mitochondria. In MCF-7 treated cells, it has been observed a reduction in mitochondrial membrane potential, a down regulation of the anti-apoptotic marker Bcl-2 and an increase of Bax and Bad, leading to release of cytochrome C and PARP cleavage. Less consistent effects are recorded in MDA-MB-231 cells, in which the greater production of ROS, compared to MCF-7cells, involves an inflammatory response (activation of p-STAT3, increased levels of COX2). Conclusions Our results have demonstrated that in MCF-7 cells the Valproic Acid is a suitable drug to arrest cell growth, to address apoptosis and mitochondrial perturbations, all factors that are important in determining cell fate and health. In a triple negative MDA-MB 231 cells, valproate directs the cells towards the inflammatory response with a sustained expression of antioxidant enzymes. Overall, the not always unequivocal data between the two cellular phenotypes indicate that further studies are needed to better define the use of the drug, also in combination with other chemotherapy, in the treatment of breast tumors.

In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER

“…MCF-7 cells and MDA-MB-231 cell were subjected to treatments with 6 and 37 to corroborate these compounds’ ability to inhibit cell proliferation. Outlined above, MCF-7 (ER and PR ( +) and MDA-MB-231 (ER, PR, and HER2 (−) cell lines were considered as models of the most common and aggressive subtype of breast cancer according to their molecular expression pattern, in addition to a deregulated Bcl-2 activity promoting an anti-apoptotic effect 62 , 63 . As is depicted in Fig.…”

Ricinodendron heudelotii (Euphorbiaceae) seed oil prevents DMBA-induced breast cancer under menopause-like conditions in Wistar rats

“…Additionally, the MDA-MB 231 are triple-negative cancer cells (-ER/- PR/- E-Catherin) in which, the protein have mutated, suggesting that the difference in anti-proliferative efficacy between the tested cell lines could be attributable to one of these pathways. In the case of MDA-MB-231 cells, the growth-inhibiting effects of phytoestrogens may be mediated through the modulation of multiple signalling pathways, including the extracellular matrix (ECM), adhesion, cell cycle, chemokine and cytokine, PI3K/AKT, STAT, TGF-β, MAPK, NF-κB, RAS/Rho, DNA repair, and apoptosis signals ( Giordano et al, 2023 ).…”

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

“…Giordano et al demonstrated that VPA inhibits the proliferation of MDA-MB 231 and MCF-7 cells by arresting the cell cycle at the G0/G1 phase through the generation of ROS from mitochondria. Furthermore, VPA induces apoptosis by releasing cytochrome c and activating poly (ADP-ribose) polymerase (PARP), achieved through the downregulation of Bcl2 and the upregulation of Bax and Bad [78]. In a separate study, Injinari et al experimentally demonstrated that VPA induces apoptosis in MDA-MB-231 and MCF-7 cells by reducing the expression of HDAC by increasing the expression of miR-34a and 520 h. Additionally, VPA elicited cytotoxicity in these cells by enhancing lipid peroxidation [79].…”