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

Abstract

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 4 nM 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-a was more significantly decreased than other PKC isotypes at this concentration. The PKC-a-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-a-dependent CDC23 inhibition.

CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia

“…Some therapeutics targeting IM resistance, including staurosporine, 31 divalproex sodium, 12 and panobinostat, 4 were tested. Generally, it is suggested that IM resistance is related to BCR–ABL in CML.…”

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

“…The short hairpin RNA (siRNA) transfection assay was carried out as previously described (Ma et al, 2018). Three pairs of Control siRNA and Alox5‐siRNA were purchased from V‐soloid Biological Technology Co., Ltd. All TKIs‐resistant cell lines were transfected with siRNAs at 60% confluence using lipofectamine 2000 (Invitrogen Corp.) according to the manufacturer's instructions.…”

Targeting Protein Kinase C for Cancer Therapy

“…Staurosporine is a natural and water-soluble pan-inhibitor of PKC. It has been demonstrated that staurosporine could selectively reverse chronic myeloid leukemia resistance to imatinib by inhibiting PKCα-dependent CDC23 inhibition and arresting the cell cycle in the G2/M phase [ 97 ]. Midostaurin (PKC412, CGP41251, N-benzoylstaurosporine), a semi-synthetic derivative of staurosporine, shows stronger inhibition on cPKC than nPKC and is inactive towards PKCζ.…”