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Review
. 2014 Mar;46(3):240-53.
doi: 10.1093/abbs/gmt142. Epub 2013 Dec 29.

Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

Xiubao Chang  1 , Yuanxiao Zhu, Changxin Shi, A Keith Stewart
Affiliations
Review

Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

Xiubao Chang et al. Acta Biochim Biophys Sin (Shanghai). 2014 Mar.

Abstract

Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields.

Keywords: E3 ubiquitin ligase; cancer treatment; cereblon; immunomodulatory drugs; multiple myeloma.

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Figures

Figure 1.
Figure 1.
Diagram of immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomideBlack shows the common structure whereas red shows the unique carboxyl group or amino group in each of these compounds.
Figure 2.
Figure 2.
Diagram of E3 ubiquitin ligase complex-mediated degradation of CRBN direct downstream substratesCRBN recognizes its direct downstream substrates and recruit them for E3 ubiquitin ligase-mediated ubiquitination. These mono-ubiquitinated substrates will be further poly-ubiquitinated, leading to proteasome-mediated degradation. Cul 4 represents Cullin 4A or Cullin 4B; Rbx1, ring box 1; E2, E2 ubiquitin-conjugating enzyme; Ubi, ubiquitin; DDB1, damaged DNA-binding protein 1; CRBN, cereblon; Sub A, B, C, CRBN direct downstream substrates A, B, or C.
Figure 3.
Figure 3.
Diagram of immunomodulatory drug (IMiD) effectsUpon IMiD binding, the binding of CRBN direct downstream substrates could be altered. If the binding of IMiD to CRBN decreases the binding of CRBN direct downstream substrates, it will prevent ubiquitination of these substrates, leading to accumulation of these CRBN direct downstream substrates. However, if the binding of IMiD to CRBN enhances the binding of CRBN direct downstream substrates (the diagram did not show this enhancement effect), it may facilitate ubiquitination of these substrates, leading to degradation of these CRBN direct downstream substrates. Altered steady state of the CRBN direct downstream substrates may affect the expression of CRBN indirect downstream factors that may elicit variant effects including immunomodulatory activity, anti-angiogenic activity, intervention of cell surface adhesion molecules, pro-apoptotic effect, cell cycle arrest, inhibition of cell migration and metastasis, anti-inflammatory activity and anti-proliferation activity, etc.
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