Tang Sishi, Liu Jing, Li Fangfang, Yan Yuhan, Long Xinyi, Fu Yunfeng
Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Heliyon. 2024 Jul 10;10(14):e34397. doi: 10.1016/j.heliyon.2024.e34397. eCollection 2024 Jul 30.
Multiple myeloma (MM) is an incurable malignancy of plasma cells that is sensitive to T-5224, an AP-1 inhibitor. Previous study indicated that T-5224 inhibits proliferation and induces apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated ferroptosis induced by T-5224 in MM. Therefore, we further investigated the mechanism by which T-5224 kills MM cells. We observed that T-5224 exhibits antimyeloma properties both in vitro and in vivo. T-5224-induced MM cell death was reversed by the ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels of the key ferroptosis regulators GPX4 and SLC7A11 were decreased by T-5224 in MM cells. Furthermore, T-5224 reduced the phosphorylation of PI3K and AKT signaling pathway components, ultimately causing MM cell death. Using 740 Y-P, a PI3K activator, and Fer-1, a ferroptosis inhibitor, we discovered that T-5224 induces ferroptosis through the PI3K/AKT pathway. Bortezomib (BTZ), an FDA-approved drug for MM treatment, can be administered in combination with other agents. We evaluated the synergistic effect of BTZ combined with AP-1 inhibitors on MM in vivo. Our findings provide a better theoretical basis for the potential mechanism of T-5224 and a new perspective on MM treatment.
多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，对AP - 1抑制剂T - 5224敏感。先前的研究表明，T - 5224可抑制MM细胞的增殖并诱导其凋亡。然而，高死亡率的原因仍无法完全解释。迄今为止，尚无研究调查T - 5224在MM中诱导的铁死亡。因此，我们进一步研究了T - 5224杀死MM细胞的机制。我们观察到T - 5224在体外和体内均表现出抗骨髓瘤特性。铁死亡特异性抑制剂铁抑素 - 1（Fer - 1）可逆转T - 5224诱导的MM细胞死亡。T - 5224可降低MM细胞中关键铁死亡调节因子GPX4和SLC7A11的蛋白水平。此外，T - 5224降低了PI3K和AKT信号通路成分的磷酸化，最终导致MM细胞死亡。使用PI3K激活剂740 Y - P和铁死亡抑制剂Fer - 1，我们发现T - 5224通过PI3K/AKT途径诱导铁死亡。硼替佐米（BTZ）是一种经FDA批准用于治疗MM的药物，可与其他药物联合使用。我们评估了BTZ与AP - 1抑制剂联合对MM的体内协同作用。我们的研究结果为T - 5224的潜在机制提供了更好的理论基础，并为MM治疗提供了新的视角。
