Abstract
Multiple myeloma (MM) is a plasma cell neoplasm characterized for its fast evolution and for being practically incurable, presenting a strong need for the development of therapies to target it. Among those under study are lenalidomide and arsenic trioxide (ATO) which show individual clinical promise, although never tested together. However, the combination of ATO with thalidomide, another immunomodulatory drug and lenalidomide’s structural albeit less potent analog, have been tried clinically with some success. Therefore, we investigated the effect the combination of lenalidomide and ATO have on the MM-derived U266 and RPMI 8226 cell lines. We observed that both compounds have separate, non-interfering, anti-myeloma mechanisms with ATO demonstrating strong cytotoxic effects while lenalidomide’s role remains cytostatic and immunomodulatory. However, ATO decreases cdc25c, which helps sensitize cells to lenalidomide effects enhancing the efficacy of their interaction. Mechanistically the combination of these two agents decreased the expression of MDM2, without affecting p53 activation or its expression. Therefore, this short study provides the foundation to continue mechanistic studies of the combination of lenalidomide and ATO as a foundation for future clinical application.
Highlights
Multiple myeloma (MM) is a plasma cell neoplasm generally derived from one clone in the bone marrow and characterized by skeletal destruction, renal failure, anemia, and hypercalcemia [1,2]
In order to compare in vitro the individual or combined effect of these drugs’ on MM cells we initially investigated the effects of arsenic trioxide (ATO), lenalidomide of their combination on the viability the MM cell lines U266 and 8226
While it can normally overcome the anti-apoptotic effect of interleukin-6, a critical cytokine for the growth and progression of myeloma cells, its reduction by lenalidomide can help ATO clinically where the interaction with the tumor microenvironment hampers the killing of malignant cells specially since it is not its only target [21]
Summary
Multiple myeloma (MM) is a plasma cell neoplasm generally derived from one clone in the bone marrow and characterized by skeletal destruction, renal failure, anemia, and hypercalcemia [1,2]. It accounts for 1% of all malignancies, and it is the second most common hematological malignancy in the United States where the overall incidence rate is 4.4/100,000/year, remains largely incurable and has a decreased survival post-diagnosis demonstrating the dire need for therapies that can treat or eventually decimate the tumor [3,4]. We have recently demonstrated that one of the main mechanisms of lenalidomide cytotoxicity
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