Low-dose staurosporine selectively reverses BCR-ABL-independent IM resistance through PKC-α-mediated G2/M phase arrest in chronic myeloid leukaemia.

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.