Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia

Abstract

Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680–induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680–sensitive leukemia patients. VX-680–induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment.

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…Several reports have shown that pharmacologic inhibition of Aurora A leads to apoptosis and our results suggest that this may due in part to mitotic stabilization of Bim. 34,50,51 Interestingly, Li et al conclusively demonstrated that apoptosis induced by Aurora A inhibition occurs through the intrinsic mitochondrial pathway requiring the activity of either Bax or Bak. 34 This is consistent with the activation of a BH3-only protein such as Bim, which functions in part by activating pro-apoptotic Bcl-2 family members Bax and Bak.…”

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

“…9,10 Our previous studies suggest that targeting AURKA may be of therapeutic use, leading to apoptosis in acute myeloid leukemia and tongue squamous cell carcinoma. 11,12 Therefore, AURKA is considered a promising molecular target for cancer therapy.…”

Aurora‐A activation, correlated with hypoxia‐inducible factor‐1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma

“…Combined with docetaxel, Aurora-A inhibition suppressed 44.0% tumor growth in esophageal squamous cell carcinoma. (29) Indeed, Aurora-A inhibitor VX-680 (MK-0457) showed a powerful capacity for suppressing tumor growth not only in leukemia, (38,39) but also in solid tumors (pancreas, prostate, and colon cancers). (40) In laryngeal squamous cell carcinoma, VX-680 effectively sensitized 20-60% of cells to X-ray irradiation and prevented 50% of cells from migrating to distant areas by attenuating AKT1/2 signaling.…”