Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions

The treatment of multiple myeloma (MM) patients has been dramatically changed by the introduction of new agents; however, many patients relapse. Hypoxia is a critical component of the bone-marrow microenvironment. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) is responsible for maintaining cellular levels of fructose-2,6-bisphosphate, which regulates glycolysis. We found that the gene expressions of PFKFB3 and PFKFB4 were elevated under hypoxic conditions. Treatments with the PFKFB3 inhibitor, PFK158, and PFKFB4 inhibitor, 5MPN, were found to inhibit the growth of myeloma cells. The combined treatment of myeloma cells with carfilzomib and PFK158 or 5MPN was more cytotoxic than either drug alone. Caspase 3/7 activity and cellular cytotoxicity were also increased. In addition, the combined treatment was effective in the bortezomib-resistant cell line. Our data also suggest that administration of PFKFB3 and PFKFB4 inhibitors may be a powerful strategy against myeloma cells and to enhance the cytotoxic effects of proteasome inhibitors in hypoxic conditions.

Automated summary

The treatment of multiple myeloma has been improved with the introduction of new drugs, but relapse is still common. Hypoxia plays a crucial role in the bone marrow microenvironment. Inhibitors of PFKFB3 and PFKFB4 show potential in inhibiting myeloma cell growth and enhancing cytotoxicity. Combination treatment with proteasome inhibitors and PFKFB inhibitors has shown enhanced cytotoxic effects.