Low-dose staurosporine selectively reverses BCR-ABL-independent IM resistance through PKC-α-mediated G2/M phase arrest in chronic myeloid leukaemia
Low-dose staurosporine selectively reverses BCR-ABL-independent IM resistance through PKC-α-mediated G2/M phase arrest in chronic myeloid leukaemia
复制标题
低剂量十字孢菌素通过 PKC-α 介导的慢性粒细胞白血病 G2/M 期阻滞选择性逆转 BCR-ABL 独立的 IM 耐药性
DOI：
10.1080/21691401.2018.1490310
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发表时间：
2018-01-01
影响因子：
5.8
通讯作者：
Wang, Jishi
中科院分区：
文献类型：
--
作者：
Ma, Dan;Wang, Ping;Wang, Jishi
伊马替尼（IM）耐药已成为治疗复发性慢性粒细胞白血病（CML）患者的关键问题，因此需要新的治疗方法。蛋白激酶C（PKC）的各种亚型在CML中上调，并与BCR-ABL调节几个信号通路有关，这些信号通路对恶性细胞转化至关重要。然而，它仍然是未知的，是否PKC同种型发挥关键作用，在IM耐药。因此，我们在此使用PKC泛抑制剂星形孢菌素（St）。为了保护正常细胞免受损伤，使用适当剂量的St，在该剂量下，IM耐药的CML细胞与IM组合被选择性地杀死，而正常细胞存活。4 nM St可逆转CML细胞的IM耐药性，主要依赖于G2/M期阻滞。细胞周期相关蛋白p21、CDK 2、cyclin A和cyclin B表达下调。同时，在此浓度下，PKC-比其他PKC亚型更显著地降低。PKC依赖的G2/M期阻滞是由下调有丝分裂进程的重要调节因子CDC 23诱导的。低剂量St也逆转了体内IM抵抗。总之，低剂量St通过PKC依赖的CDC 23抑制，将细胞周期阻滞在G2/M期，选择性地增加IM耐药CML对IM的敏感性。
Imatinib (IM) resistance has become a critical problem for the treatment of patients with relapsed chronic myeloid leukaemia (CML), so novel therapies are in need. Various isotypes of protein kinases C (PKCs) are up-regulated in CML and related with BCR-ABL regulating several signalling pathways that are crucial to malignant cellular transformation. However, it is still unknown whether PKC isotypes play crucial roles in IM resistance. Therefore, we herein used a PKC pan-inhibitor staurosporine (St). To protect normal cells from damage, a proper dose of St was used, at which IM-resistant CML cells were selectively killed in combination with IM but normal cells survived. The IM resistance of CML cells was best reversed by 4nM St alone, mainly depending on the G2/M phase arrest. Cell cycle-related proteins p21, CDK2, cyclin A and cyclin B were down-regulated. Meanwhile, PKC- was more significantly decreased than other PKC isotypes at this concentration. The PKC--dependent G2/M phase arrest was induced by down-regulation of CDC23, an important regulator of mitotic progression. Low-dose St also reversed IM resistance in vivo. In conclusion, low-dose St selectively increased the sensitivity of IM-resistant CML to IM by arresting cell cycle in the G2/M phase through PKC--dependent CDC23 inhibition.