Anticancer activity in human multiple myeloma U266 cells: synergy between cryptotanshinone and arsenic trioxide

Arsenic trioxide (As2O3) has been recently established as one of the most effective drugs for the treatment of patients with acute promyelocytic leukemia. However, it has exhibited to be less efficient for the non-promyelocytic leukaemia or other types of malignant tumors. The purpose of the present study was to explore new therapeutic strategies based on As2O3 for human multiple myeloma. Here, we first report cryptotanshinone (CPT) and As2O3 synergy for enhanced cytotoxicity in human multiple myeloma U266 cells. In particular, the apoptosis related proteins (e.g., cleaved poly (ADP-ribose) polymerase (PARP), caspase-3 and -9) were significantly increased by the combination treatment (iAs(III) + CPT), whereas, the expression of survival proteins such as Bcl-2 and survivin was suppressed, suggesting that the induction of apoptosis through mitochondrial-mediated apoptotic pathway. In addition, there were no appreciable effects observed in cells after exposure to either As2O3 or CPT alone. In order to better understand the molecular mechanism, we further determined the phosphorylation of STAT3, JNK, ERK and p38. Interestingly, phosphorylation of JNK and p38 were remarkably induced by combination treatment, and no significant inhibition of STAT3 or ERK was observed. In addition, induction of apoptosis in human multiple myeloma cells was partially abrogated only by pretreatment with JNK inhibitor and not by p38 inhibitor, suggesting that JNK pathway may play an important role in induction of apoptosis by the combination of iAs(III) and CPT. Further studies are needed to evaluate this synergistic anticancer effect in vivo. In the near future, this new approach might be used clinically for multiple myeloma (MM) treatment.