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 IC50by 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.
背景：多药耐药性（MDR）主要由P-糖蛋白（P-gp）介导的药物外排驱动，是癌症治疗中的重大挑战，常导致化疗失败及患者预后不良。本研究旨在探讨临床已批准的钙通道阻滞剂马尼地平（MA）通过活化T细胞核因子2（NFAT2）调控钙信号通路，逆转P-gp介导的MDR的潜力。方法：采用过表达ABCB1的紫杉醇（PTX）耐药肿瘤体外及体内模型评估MA的抗MDR效应，并利用NFAT2 siRNA探究其作用机制。结果：在无毒浓度范围（0.6–5.4 μM）内，MA能显著增强耐药性结直肠癌细胞（HCT-8/T）和非小细胞肺癌细胞（A549/T）对PTX的敏感性，使体外模型中PTX的IC50降低最高达1328倍。机制研究表明，MA在不改变P-gp表达的情况下抑制其外排功能：阿霉素和Flutax-2的细胞内蓄积分别增加2.3倍和3.1倍，且对ATP酶活性呈剂量依赖性调控（EC50= 4.16 μM）。值得注意的是，MA可降低细胞内钙水平（降幅52%，p<0.001），并下调耐药细胞中过表达的癌基因NFAT2。在A549/T移植瘤模型中，MA（3.5 mg/kg）与PTX联用可协同抑制68%的肿瘤生长（p<0.001），且未引起明显体重下降。结论：综上所述，MA作为一种新型NFAT2抑制剂，通过调控钙信号通路克服P-gp介导的MDR，这为其临床应用研究提供了新方向。
Targeting NFAT2 for Reversing the P-gp-Mediated Multidrug Resistance to Paclitaxel by Manidipine
肿瘤(癌症)患者之家