Acute leukemia is a neoplastic disease characterized by a rapid accumulation of primitive hematopoietic cells. MPT0B392 acts as a potential anticancer drug for the treatment of acute leukemia. MPT0B392 is a strong microtubule binding and depolymerizing agent but not a p-gp substrate. To determine the antitumor activity of MPT0B392, Min-Wu Chao, et al performed an MTT assay in leukemic cell lines. MPT0B392 inhibits the cell viability of HL60, MOLT-4, and CCRF-CEM cells with IC50 values of 0.02, 0.03, and 0.02 μM, respectively, at 48 h. This effect is in a concentration-dependent manner. MPT0B392 shows a better cytotoxic effect than Vincristine in primary acute myeloid leukemia (AML) cells.

Further investigation reveals that MPT0B392 triggers induction of the mitotic arrest, followed by mitochondrial membrane potential loss and caspases cleavage by activation of JNK. MPT0B392 causes mitotic arrest and ultimately leads to apoptosis. Apoptosis is a process by which cells undergo organized self-destruction without eliciting an inflammatory response. In addition, MPT0B392 enhances the cytotoxicity of Sirolimus in Sirolimus-resistant acute leukemic cells through inhibition of Akt/mTOR pathway and Mcl-1 protein expression. Moreover, immunochemistry staining and tumor homogenates show that MPT0B392 induces apoptosis in cancer cells, demonstrated by detection of positive staining of cleavage caspase 3.

On the other hand, MPT0B392 induces apoptosis in xenograft models. The effects of oral administration of MPT0B392 show relative potent anti-leukemia activity in an in vivo xenograft model. MPT0B392 treatment results in significant tumor growth delay (83.3%) and tumor volume inhibition in MOLT-4 and HL60 xenograft model, without loss of body weight. Taken together, these data suggest that MPT0B392 exhibits anticancer activity with less cytotoxicity both in vitro and in vivo.

Chao MW, et al. An oral quinoline derivative, MPT0B392, causes leukemic cells mitotic arrest and overcomes drug resistant cancer cells. Oncotarget. 2017 Apr 25;8(17):27772-27785.