Department of Chinese Medicine of E-Da Cancer Hospital, I-Shou University, Koahsiung, Taiwan, R.O.C.
School of Chinese Medicine for Post-Baccalaureate, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C.
Anticancer Res. 2024 Mar;44(3):1121-1130. doi: 10.21873/anticanres.16907.
BACKGROUND/AIM: Chronic lymphocytic leukemia is a slowly-progressing disease in which symptoms often do not manifest until years after disease onset. In advanced stages, infection and bleeding are common. Past studies have shown that the interaction between CDK4/6 inhibitors and chemotherapy drugs can enhance the anti-tumor efficacy of drugs and limit toxicity. Therefore, in this study, the treatment effects of combining the CDK4/6 inhibitor LEE011 with chemotherapy drugs bendamustine or hydroxyurea were investigated in vitro.
The mouse lymphocytic leukemia cell line L1210 was treated with LEE011 combined with hydroxyurea or bendamustine. Western blot and flow cytometry were performed to elucidate the mechanisms behind tumor suppression.
LEE011 combined with hydroxyurea or bendamustine significantly inhibited proliferation of L1210 cell lines in a concentration- and time-dependent manner as well as increased the arrest of cells in G and S phases. The combination of LEE011 with hydroxyurea also reduced the phosphorylation of Rb while increased the expression of total Rb protein. Furthermore, reduced expression of GPX4, which is a key protein in ferroptosis, indicates that the tumor suppression effects of this drug combination could involve ferroptosis.
CDK4/6 inhibitor LEE011 treatment alone may not be a suitable treatment option for lymphocytic leukemia; however, our findings in vitro support the combination of LEE011 with chemotherapy drugs to enhance anti-tumor activity in lymphocytic leukemia.
背景/目的：慢性淋巴细胞白血病是一种进展缓慢的疾病，其症状通常在发病多年后才会出现。在晚期，感染和出血很常见。过去的研究表明，CDK4/6 抑制剂与化疗药物的相互作用可以增强药物的抗肿瘤疗效并限制毒性。因此，在这项研究中，体外研究了 CDK4/6 抑制剂 LEE011 与化疗药物苯达莫司汀或羟基脲联合使用的治疗效果。
用 LEE011 联合羟基脲或苯达莫司汀处理小鼠淋巴细胞白血病细胞系 L1210。通过 Western blot 和流式细胞术阐明肿瘤抑制的机制。
LEE011 联合羟基脲或苯达莫司汀可显著抑制 L1210 细胞系的增殖，呈浓度和时间依赖性，并使细胞停滞在 G 和 S 期。LEE011 与羟基脲联合还降低了 Rb 的磷酸化，同时增加了总 Rb 蛋白的表达。此外，关键的铁死亡蛋白 GPX4 的表达降低表明，这种药物联合的肿瘤抑制作用可能涉及铁死亡。
CDK4/6 抑制剂 LEE011 单独治疗可能不是淋巴细胞白血病的合适治疗选择；然而，我们在体外的发现支持 LEE011 与化疗药物联合使用，以增强淋巴细胞白血病的抗肿瘤活性。
