Co-targeting Aurora kinase A and Bcl-2 synergistically inhibits the viability in double-hit lymphoma cells

Kong, Ling Zhe; Jia, Xiao; Zheng, Shu; Qiu, Li; Li, Lan Fang; Zheng, Qian; Zhou, Shujun; Liu, Xian Ming; Ren, Xiu Bao; Meng, Bin; Fu, Kai; Wang, Ping; Li, Linyu; Zhang, Hui Lai

doi:10.21037/tcr.2017.06.41

Cited by 1 publication

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“…Bcl-2 inhibition in other clinical settings, notably hematologic malignancies, have also proven effective when combined with other therapies such as rituximab, bendamustine, and hypomethylating agents [11], [12], [14]. Furthermore, the combination Bcl-2 inhibition with MLN8237 appears efficacious for double hit lymphoma in vitro [37]. Thus, dual therapy of Bcl-2 inhibitors with a second therapeutic class, including AKA inhibitors, are promising for a variety of malignancies including pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Novel Synergistic Combination of Mitotic Arrest and Promotion of Apoptosis for Treatment of Pancreatic Adenocarcinoma

Duan

Chinn

et al. 2019

Translational Oncology

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The BCL-2 family of proteins, including anti-apoptotic members BCL-2, BCL-XL and MCL-1, are part of a complex network that controls apoptosis. BH3-mimetics such as ABT-263 inhibit anti-apoptotic BCL-2 proteins and have been developed as potential cancer therapeutics. Aurora Kinase A (AKA) is over-expressed in pancreatic cancer (PC) and controls G2-M transition during mitosis and AKA inhibitors have been developed that induce mitotic arrest. We hypothesized that mitotic arrest induced by AKA inhibition may sensitize PC to accelerated apoptosis by a BH3-mimetic. Our results demonstrated that ABT-263 plus MLN8237 treatment showed greater activity than either single drug alone, as well as strong synergism, in the inhibition of growth of pancreatic cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) and PC patient-derived organoids (PDOs). The higher efficacy of combination treatment was attributable to the higher levels of induction of apoptosis and reduction of MCL-1 in PC cells and PDOs. In addition, combination therapy was more effective than single drug in the suppression of tumor growth in AsPC-1 xenograft mouse models. Together, our findings suggest that combination therapy with ABT-263 and MLN8237 should be considered for further exploration as a novel treatment of deadly PC disease.

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