Targeting NFAT2 for Reversing the P-gp-Mediated Multidrug Resistance to Paclitaxel by Manidipine

TL;DR

Manidipine, a blood pressure drug, can reverse cancer drug resistance by targeting a protein called NFAT2, making chemotherapy more effective.

Contribution

Manidipine is shown to reverse P-gp-mediated multidrug resistance in cancer by inhibiting NFAT2 and modulating calcium signaling.

Findings

Manidipine significantly sensitizes drug-resistant cancer cells to paclitaxel by reducing P-gp efflux activity.

Manidipine inhibits tumor growth in a mouse model of drug-resistant cancer without harmful side effects.

Manidipine reduces intracellular calcium levels and downregulates NFAT2, a protein linked to drug resistance.

Abstract

Multidrug resistance (MDR) is a major problem in cancer treatment, often caused by a protein called P-glycoprotein (P-gp) that pumps chemotherapy drugs out of cancer cells. This makes treatments less effective and leads to poor outcomes for patients. In this study, we investigated manidipine (MA), a drug used to treat high blood pressure, to see if it could reverse this resistance. We found that MA, at safe doses, can make drug-resistant cancer cells more sensitive to chemotherapy drugs like paclitaxel. It does this by changing calcium levels inside cells and reducing the activity of a protein called NFAT2, which is linked to resistance. In experiments, MA significantly improved the effectiveness of chemotherapy and reduced tumor growth in mice, without causing harmful side effects. Our findings suggest that MA could be a promising new approach to overcoming drug resistance in cancer treatment.

Background: Multidrug resistance (MDR), primarily driven by P-glycoprotein (P-gp)-mediated drug efflux, presents a significant challenge in cancer therapy, contributing to chemotherapy failure and poor patient outcomes. Objectives: In this study, we explored the potential of manidipine (MA), a clinically approved calcium channel blocker, to reverse P-gp-mediated MDR through modulation of calcium signaling via nuclear factor of activated T cells 2 (NFAT2). Methods: Paclitaxel (PTX) resistance ABCB1-overexpressing cancer in vitro and in vivo were used for evualting the anti-MDR effects of MA, as well as the underlying mechanism with siRNA of NFAT2. Results: We found that MA at non-toxic concentrations (0.6–5.4 μM) significantly sensitize drug-resistant colorectal (HCT-8/T) and non-small cell lung (A549/T) cells to PTX, reducing its IC50 by up to 1328-fold in vitro models. Mechanistically, MA inhibited P-gp efflux activity without altering its expression, as shown by an increased intracellular accumulation of doxorubicin and Flutax-2 (2.3- and 3.1-fold, respectively) and dose-dependent modulation of ATPase activity (EC50 = 4.16 μM). Notably, MA reduced intracellular calcium levels (52% reduction, p < 0.001) and downregulated NFAT2, an oncogene overexpressed in resistant cells. In vivo, MA (3.5 mg/kg) synergizes with PTX to inhibit tumor growth by 68% (p < 0.001) in A549/T xenograft model, without an observable decrease in weight. Conclusions: In sum, all these results position MA as a novel NFAT2 inhibitor to overcome P-gp-mediated MDR via modulating calcium signaling, which points to further investigation for its clinical applications.

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