(ChemotherapyAdvisor) – Clinical trials of combination therapies for multiple myeloma may soon involve evaluation of obatoclax and flavopiridol, according to a team of US-based researchers. This conclusion is based on a study entitled “CDK Inhibitors Upregulate BH3-Only Proteins to Sensitize Human Myeloma Cells to BH3 Mimetic Therapies,” which was published in Cancer Research on August 15.
The design of this study is based on previous evidence on the mechanism of action of 2 classes of anti-cancer drugs: BH3 mimetics and cyclin-dependent kinase (CDK) inhibitors. BH3 mimetics kill cancer cells work by inhibiting activity of the Bcl-2 family proteins. CDK inhibitors help BH3 mimetics to kill cancer cells by interfering with the activity of a specific Bcl-2 family member, Mcl-1.
In this study, the investigators aimed to determine the precise mechanism of BH3 mimetics’ effect on Mcl-1 by evaluating interactions between CDK inhibitor flavopiridol and the BH3 mimetic obatoclax in multiple myeloma cells.
When the investigators co-administered flavopiridol and obatoclax, the inhibitors killed both drug-naïve and drug-resistant multiple myeloma cells. Further investigation into the mechanisms of these 2 inhibitors demonstrated that flavopiridol decreases the expression of Mcl-1 and that obatoclax prevents Mcl-1 from being recovered from the effects of flavopiridol. Other experiments in this study corroborated these findings.
Based on these findings, the investigators concluded that these experiments will impact the design of clinical trial of “BH3 mimetic-based therapies that are presently being studied intensively for the treatment of diverse hematopoietic malignancies, including lethal multiple myeloma.”