Sun Rong, Tanino Ryosuke, Tong Xuexia, Haque Eshat Fahmida, Amano Yoshihiro, Isobe Takeshi, Tsubata Yukari
Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Izumo, Japan.
Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, China.
Transl Lung Cancer Res. 2022 Apr;11(4):543-559. doi: 10.21037/tlcr-21-765.
Acquired pemetrexed resistance leads to treatment interruption in patients with malignant pleural mesothelioma (MPM). Insulin-like growth factor-I receptor (IGF-1R) inhibitor is a candidate for treating pemetrexed-naïve MPM. However, the efficacy of cytotoxic and targeted drugs in acquired-pemetrexed resistant MPM is unclear. We explored anticancer drugs, including the IGF-1R inhibitor picropodophyllin, against acquired pemetrexed-resistant MPMs.
Acquired pemetrexed-resistant human MPM cell lines, named as H2452/PEM and 211H/PEM after their parental lines H2452 and 211H, respectively, were established by exposure to pemetrexed . Picropodophyllin and siRNA for IGF-1R knockdown were used to evaluate the efficacy of IGF-1R inhibition. Immunofluorescence was used to evaluate microtubule localization. The efficacy of picropodophyllin was evaluated in 3-dimensional MPM models.
The acquired pemetrexed-resistant MPM lines retained their resistance after the removal of culture treatment. IGF-1R levels in H2452/PEM cells were higher than those in H2452 cells but not in 211H/PEM cells compared to the respective parental line. Picropodophyllin induced sub-G1 arrest in H2452/PEM cells but induced G2/M phase arrest in 211H/PEM cells, leading to caspase-independent cell death in the two acquired pemetrexed-resistant MPM lines. Although picropodophyllin inhibited phosphorylation of IGF-1R, specific inhibition of IGF-1R by RNA interference did not reduce the viability of pemetrexed-resistant MPM lines. Additionally, picropodophyllin reduced the viability of both IGF-1R knockdown pemetrexed-resistant MPM cells. Picropodophyllin was cytotoxic in acquired-pemetrexed-resistant MPM lines because of inhibition of microtubule formation and induction of aberrant mitosis. Moreover, combination treatment with picropodophyllin and vinorelbine synergistically affected the pemetrexed-resistant MPM lines but not the parental lines. Furthermore, we observed a similar efficacy of picropodophyllin in 3-dimensional pemetrexed-resistant MPM models.
Picropodophyllin may offer novel therapeutic properties for treating acquired pemetrexed-resistant MPM. Targeting tubulin may be an important strategy in the treatment of MPM after the discontinuation of pemetrexed.
获得性培美曲塞耐药导致恶性胸膜间皮瘤（MPM）患者的治疗中断。胰岛素样生长因子-I受体（IGF-1R）抑制剂是治疗初治MPM的候选药物。然而，细胞毒性药物和靶向药物在获得性培美曲塞耐药MPM中的疗效尚不清楚。我们探索了包括IGF-1R抑制剂鬼臼苦素在内的抗癌药物对获得性培美曲塞耐药MPM的作用。
通过暴露于培美曲塞建立获得性培美曲塞耐药的人MPM细胞系，分别命名为H2452/PEM和211H/PEM，其亲本细胞系分别为H2452和211H。使用鬼臼苦素和针对IGF-1R敲低的小干扰RNA（siRNA）来评估IGF-1R抑制的疗效。采用免疫荧光法评估微管定位。在三维MPM模型中评估鬼臼苦素的疗效。
去除培养处理后，获得性培美曲塞耐药的MPM细胞系仍保留其耐药性。与各自的亲本细胞系相比，H2452/PEM细胞中的IGF-1R水平高于H2452细胞，但211H/PEM细胞中的IGF-1R水平不高于211H细胞。鬼臼苦素在H2452/PEM细胞中诱导亚G1期阻滞，但在211H/PEM细胞中诱导G2/M期阻滞，导致这两种获得性培美曲塞耐药的MPM细胞系发生非半胱天冬酶依赖性细胞死亡。尽管鬼臼苦素抑制了IGF-1R的磷酸化，但RNA干扰对IGF-1R的特异性抑制并未降低培美曲塞耐药MPM细胞系的活力。此外，鬼臼苦素降低了两种IGF-1R敲低的培美曲塞耐药MPM细胞的活力。鬼臼苦素在获得性培美曲塞耐药的MPM细胞系中具有细胞毒性，因为它抑制微管形成并诱导异常有丝分裂。此外，鬼臼苦素与长春瑞滨联合治疗对培美曲塞耐药的MPM细胞系有协同作用，但对亲本细胞系无协同作用。此外，我们在三维培美曲塞耐药MPM模型中观察到鬼臼苦素具有相似的疗效。
鬼臼苦素可能为治疗获得性培美曲塞耐药的MPM提供新的治疗特性。在培美曲塞停用后，靶向微管蛋白可能是治疗MPM的重要策略。
