Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, 31111 Tanta, Egypt.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Biomed Pharmacother. 2023 Aug;164:114907. doi: 10.1016/j.biopha.2023.114907. Epub 2023 May 27.
Carfilzomib (CFZ) is a proteasome inhibitor approved for relapsed/refractory multiple myeloma (MM) but its clinical use is limited by cardiovascular toxicity. The mechanisms of CFZ-induced cardiovascular toxicity are not fully understood but endothelial dysfunction may be a common denominator. Here, we first characterized the direct toxic effects of CFZ on endothelial cells (HUVECs and EA.hy926 cells) and tested whether SGLT2 inhibitors, known to have cardioprotective effects, can protect against CFZ-induced toxicity. To determine the chemotherapeutic effect of CFZ in the presence of SGLT2 inhibitors, MM and lymphoma cells were treated with CFZ with or without canagliflozin. CFZ decreased cell viability and induced apoptotic cell death in endothelial cells in a concentration-dependent manner. CFZ also upregulated ICAM-1 and VCAM-1 and downregulated VEGFR-2. These effects were associated with the activation of Akt and MAPK pathways, inhibition of p70s6k, and downregulation of AMPK. Canagliflozin, but not empagliflozin or dapagliflozin, protected endothelial cells from CFZ-induced apoptosis. Mechanistically, canagliflozin abrogated CFZ-induced JNK activation and AMPK inhibition. AICAR (an AMPK activator) protected from CFZ-induced apoptosis, and compound C (an AMPK inhibitor) abrogated the protective effect of canagliflozin, strongly suggesting that AMPK mediates these effects. Canagliflozin did not interfere with the anticancer effect of CFZ in cancer cells. In conclusion, our findings demonstrate for the first time the direct toxic effects of CFZ in endothelial cells and the associated signaling changes. Canagliflozin abrogated the apoptotic effects of CFZ in endothelial cells in an AMPK-dependent mechanism, without interfering with its cytotoxicity in cancer cells.
卡非佐米（CFZ）是一种蛋白酶体抑制剂，已被批准用于治疗复发性/难治性多发性骨髓瘤（MM），但其临床应用受到心血管毒性的限制。CFZ 诱导的心血管毒性的机制尚未完全阐明，但内皮功能障碍可能是一个共同的因素。在这里，我们首先描述了 CFZ 对内皮细胞（HUVECs 和 EA.hy926 细胞）的直接毒性作用，并测试了是否 SGLT2 抑制剂（具有心脏保护作用）可以预防 CFZ 诱导的毒性。为了确定 SGLT2 抑制剂存在时 CFZ 的化疗效果，用 CFZ 处理 MM 和淋巴瘤细胞，同时存在或不存在卡格列净。CFZ 以浓度依赖性方式降低内皮细胞的细胞活力并诱导细胞凋亡。CFZ 还上调了 ICAM-1 和 VCAM-1 并下调了 VEGFR-2。这些作用与 Akt 和 MAPK 途径的激活、p70s6k 的抑制以及 AMPK 的下调有关。卡格列净，但不是恩格列净或达格列净，可保护内皮细胞免受 CFZ 诱导的凋亡。从机制上讲，卡格列净阻断了 CFZ 诱导的 JNK 激活和 AMPK 抑制。AICAR（AMPK 激活剂）可预防 CFZ 诱导的凋亡，而化合物 C（AMPK 抑制剂）阻断了卡格列净的保护作用，强烈表明 AMPK 介导了这些作用。卡格列净不干扰 CFZ 在癌细胞中的抗癌作用。总之，我们的研究结果首次证明了 CFZ 在内皮细胞中的直接毒性作用及其相关的信号变化。卡格列净通过 AMPK 依赖性机制阻断 CFZ 在内皮细胞中的凋亡作用，而不干扰其在癌细胞中的细胞毒性。
