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GLUT4 inhibition by Ritonavir drug reduces myeloma proliferation and viability and increases chemosensitivity

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"Finally, we have demonstrated that the off-target inhibitory effect on GLUT4 of the HIV protease inhibitor ritonavir can be exploited to reduce myeloma proliferation and viability and increase chemosensitivity. Although the growth-inhibitory properties of ritonavir and related compounds saquinavir and nelfinavir toward myeloma cells have been established,49 our data demonstrate that these effects stem from inhibition of GLUT4-dependent glucose consumption.

This finding provides strong rationale for the initiation of clinical trials to assess the efficacy of ritonavir in myeloma, a repositioning that could be implemented rapidly given its approval by the FDA.

Indeed, ritonavir is currently being tested in several ongoing clinical trials in other malignancies.

The widely acknowledged presence of metabolic side effects associated with chronic ritonavir administration (which recapitulate some of the pathologies seen in GLUT4 knockout mice50) suggests that GLUT4 activity is impacted by the dosages used in HIV therapy. Although these side effects are also a concern with regard to the use of ritonavir to treat MM, we think that the chronic dosing schedule necessary to prevent HIV replication may not be required to elicit meaningful antimyeloma effects in vivo, and more flexible regimens could ameliorate the adverse metabolic impact of ritonavir on normal tissues. Furthermore, the use of ritonavir in a chemosensitizing role would entail only cyclical administration."

Reference: Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy