Department of Pharmaceutical Sciences, College of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Suwanee, GA 30024, USA.
Int J Mol Sci. 2023 Aug 9;24(16):12590. doi: 10.3390/ijms241612590.
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.
多发性骨髓瘤（MM）是一种骨髓浆细胞癌，其特征是骨病变、高钙血症、贫血和肾衰竭。硼替佐米（BTZ）是一种常用于 MM 的治疗药物，是一种蛋白酶体抑制剂，可诱导 MM 细胞凋亡。然而，高剂量的 BTZ 可能非常有毒，这表明需要一种协同药物组合来提高治疗效果。白藜芦醇（RES）是一种存在于葡萄中的酚类化合物，已被证明可抑制 MM 细胞生长。我们试图确定 BTZ 与 RES 衍生物的协同组合，并分析其对降低人 MM 细胞活力和诱导细胞凋亡的影响。BTZ 以及 RES 及其衍生物白藜芦醇（PIN）和皮考汀（PIC）均以剂量和时间依赖的方式降低 MM 细胞活力，并以剂量依赖的方式增加裂解的促凋亡蛋白多聚（ADP-核糖）聚合酶 1（PARP1）和半胱天冬酶-3 的表达。确定 5 nM BTZ 和 5 μM PIN 的组合在 MM RPMI 8226 细胞中具有协同细胞毒性作用。与单独使用化合物相比，用该组合处理 24 小时的 MM RPMI 8226 细胞显示出更高的裂解 PARP1 和半胱天冬酶-3 表达以及更高比例的凋亡细胞。该治疗还在 Transwell 模型中模拟骨髓微环境，对共培养的 MM RPMI 8226 细胞和人骨髓基质 HS-5 细胞显示出更高的诱导凋亡作用。在用 24 小时处理后，RPMI 8226 细胞中的氧化应激防御蛋白（过氧化氢酶、硫氧还蛋白和超氧化物歧化酶）的表达减少，并且抗氧化剂 N-乙酰半胱氨酸（NAC）减轻了治疗的细胞毒性作用，表明该治疗影响 RPMI 8226 细胞中的抗氧化水平。我们的结果表明，BTZ 和 PIN 的这种组合通过诱导 MM 细胞凋亡和氧化应激来协同降低 MM 细胞活力。
