Simultaneous inhibition of Chk1 and Bcl-xL induces apoptosis in vitro and represses tumour growth in an in vivo xenograft model

Abstract

We previously showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, and navitoclax, a Bcl-2 and Bcl-xL inhibitor, induced a synergistic inhibitory effect on cell proliferation in vitro. Here, we investigated the effect of the simultaneous knockdown of Chk1 and each antiapoptotic protein of the Bcl-2 family (Bcl-2, Bcl-xL, or Mcl-1) with small interfering RNAs on apoptosis in three pancreatic cancer cell lines. Only simultaneous knockdown of Chk1 and Bcl-xL induced significant apoptosis compared with single knockdown in all three cell lines. We evaluated the anti-tumour effects of combined prexasertib and navitoclax treatment in a mouse xenograft model. Treatment to control volume ratios were calculated as 63.2% for prexasertib, 79.4% for navitoclax, and 36.8% for prexasertib and navitoclax. These findings suggest that the simultaneous inhibition of Chk1 and Bcl-xL may be an effective treatment for pancreatic cancer.

Keywords:

• Chk1
• Bcl-2
• Bcl-xL
• Mcl-1
• prexasertib
• navitoclax

Disclosure statement

The authors report no conflict of interest.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Y.M. K.T. conducted the animal experiment and performed the statistical analysis. O.T. supervised the research and experiments. K.W. and M.H. reviewed the data and coordinated the writing of the manuscript. Y.M. coordinated the scientific work and the writing of the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability statement

The data that support the findings of this study are available from the corresponding author, Y.M., upon reasonable request.

Additional information

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.