Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML), a clonal hyperproliferation of immature blood cells accounts for 20% of adult leukemia cases. Reciprocal translocation of chromosomes 9 and 22, results into Bcr-Abl fusion and is responsible for expression of a tyrosine kinase protein p210(bcr/abl), which mediates several survival pathways and confer therapeutic resistance. Protein kinase C (PKC), a family of serine threonine kinases play an important role in the process of leukemogenesis. A crosstalk between Bcr-Abl and PKC signaling has been documented. Therefore, targeting p210(bcr/abl) and its associated signaling proteins using non-toxic natural means will be an effective strategy for antileukemic therapy. Aim of the present study is to investigate whether PEITC, a natural isothiocyanate in combination with imatinib mesylate (IM), a tyrosine kinase inhibitor could increase the therapeutic efficacy of IM by modulating the expression of p210(bcr/abl). Enhanced cytotoxic efficacy of IM by PEITC was further validated using another myelogenous leukemia cell line, KU812. It was observed that PEITC in combination with IM efficiently downregulated the expression of p210(bcr/abl) in chronic myelogenous leukemia cell lines (K-562). PEITC inhibited the expressions of PKCα, PKCβII and PKCζ (both phosphorylated and total form). Expression of Raf1 and ERK1/2, two important target proteins in PKC signaling cascade was diminished. The result indicated that PEITC ultimately reduced expression of Raf1 and ERK1/2 through Bcr-Abl and PKC inhibition. This result was further confirmed by UCN-01, a selective PKC inhibitor and IM; indicating an association between p210(bcr/abl) and PKC with Raf1 and ERK1/2. PEITC thus may have enormous potential in synergistic therapy of leukemia by enhancing drug efficacy.