Abstract
Previous studies have investigated the inhibitory effect of BMI-1026 on cyclin-dependent kinase 1 in vitro. However, the molecular mechanisms by which BMI-1026 treatment leads to cancer cell death remain unclear. This study was conducted to investigate the anticancer mechanisms of BMI-1026 on human renal carcinoma Caki cells. BMI-1026 induced apoptosis in association with the cleavage of poly(ADP-ribose) polymerase and pro-caspase-3 and the release of apoptosis-inducing factor and cytochrome c from mitochondria in Caki cells. BMI-1026-induced apoptosis was inhibited by the pan-caspase inhibitor z-VAD-fmk. Furthermore, BMI-1026 downregulated Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) at the transcriptional level and Mcl-1 (L) and cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the post-transcriptional level. Interestingly, Mcl-1 (L) and c-FLIP (L), but not Bcl-2 or XIAP, played important roles in BMI-1026-induced Caki cell apoptosis. Although the constitutively active form of Akt did not attenuate BMI-1026-induced apoptosis, blockade of the PI3K/Akt pathway using a subcytotoxic concentration of the PI3K/Akt inhibitor LY294002 enhanced Caki cell apoptosis induced by BMI-1026. Electrophysiological safety was confirmed by determining the cardiotoxicity of BMI-1026 via left ventricular pressure analysis. These results suggest that BMI-1026 is a potent multitarget anticancer agent with electrophysiological safety and should be further investigated.
Highlights
The human genome encodes 538 protein kinases [1], and the identification of their roles in cancer has led to extensive studies on the development and potential uses of protein kinase inhibitors for anticancer therapy [2]
Among the various targets of protein kinase inhibitors, cyclin-dependent kinases (Cdks) are promising targets for cancer therapeutics because of their important role in cancer cell proliferation via cell cycle dysregulation, which is a hallmark of cancer [3]
We investigated whether BMI-1026 induces cell cycle arrest and apoptosis in several types of human cancer cells
Summary
The human genome encodes 538 protein kinases [1], and the identification of their roles in cancer has led to extensive studies on the development and potential uses of protein kinase inhibitors for anticancer therapy [2]. To develop potent anticancer agents that inhibit Cdk activity, a large amount of research has focused on screening for ATP-competitive inhibitors and investigating the mechanisms by which they exert their anticancer effects [3]. It is important to ensure the electrophysiological safety of drugs based on reliable assessment of the potential for proarrhythmic cardiotoxicity. Such methods include QT interval prolongation, which increases the risk of torsade de pointes (TdP) [9,10,11]. TdP prolongs the QT interval of the electrocardiogram by inhibiting the human ether-à-go-go-related gene (hERG) potassium channel, which is related to the action potential and its duration in the myocardial cell membrane [12,13]. We showed that BMI-1026 induced Caki cell apoptosis by downregulating the expression of anti-apoptotic proteins Mcl-1 (L) and cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L))
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