Lenalidomide and CC-4047 Inhibit the Proliferation of Namalwa Cancer Cells While Expanding CD34⁺ Progenitor Cells. New Insights on the Combination Therapy with Certain HDAC Inhibitors for Hematological Cancers.

Clinical studies involving patients with Myelodysplastic Syndrome and Multiple Myeloma have demonstrated the efficacy of lenalidomide (CC-5013), a drug recently approved by the FDA under the commercial name of Revlimid^®, by reducing and often eliminating malignant cells while restoring bone marrow function. To better understand these clinical observations, we investigated and compared the effects of lenalidomide, and its analog CC-4047, on the proliferation of two different hematopoietic cell models: the Namalwa cancer cell line and CD34⁺ progenitor cells. We found that both compounds have anti-proliferative effect on Namalwa cells and pro-proliferative effect on CD34⁺ cells while p21^WAF−1 expression was upregulated in both cell models. In Namalwa cells, we determined that p21^WAF−1 is responsible for the inhibition of CDK2, CDK4, and CDK6 activity leading to pRb hypophosphorylation and cell cycle arrest. In contrast, in CD34⁺ progenitor cells, despite upregulated p21^WAF−1 expression, we observed an increase of the cell division rate, leading to the enhancement of CD34⁺ expansion. Finally, we found that CC-4047 and lenalidomide have synergistic effects with two different HDAC inhibitors (Valproic acid and Trichostatin A) in both increasing the apoptosis of Namalwa cells and enhancing CD34⁺ cell expansion. Taken together, our results indicate that lenalidomide and CC-4047 have opposite effects in tumor cells versus progenitor cells and could explain, at least in part, the reduction of malignant cells and the restoration of the bone marrow observed in patients undergoing lenalidomide treatment. Moreover, this study provides new insights on the cellular pathways affected by lenalidomide and CC-4047, and proposes new potential clinical uses such as bone marrow regeneration. Finally, our vitro experiments showing the efficacy of the combination of CC-4047 and lenalidomide with Valproic acid and Trichostatin A suggest that HDAC inhibitors might be ideal candidates for combination therapy by elevating the therapeutic index, versus monotherapy, to treat hematological malignancies.