A drug repositioning success: The repositioned therapeutic applications and mechanisms of action of thalidomide

Abstract

Background Thalidomide is the most teratogenic human medicine ever marketed and was associated with birth defects in approximately 10,000 children in the 1960s. The pharmacological effects of thalidomide are attributed to its anti-angiogenic, anti-inflammatory and modulatory effect on cytokines principally tumor necrosis factor-α, while the teratogenic effects are linked to two molecular targets, namely cereblon and tubulin. Teratogenicity is the gravest adverse effect of thalidomide depending on the dose and time of exposure. Nonetheless, with System for Thalidomide Education and Prescribing Safety program, the possibility of teratogenicity can be completely avoided. The sensitive period during pregnancy for thalidomide teratogenicity in humans is approximately 20-34 days after fertilization. Methods Relevant articles were identified from Google scholar and PubMed (MEDLINE) using different search strategies. Conclusion Clinical trials showed that thalidomide has been found effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy refractory endometrial cancer and pancreatic cancer, which can suggest its future therapeutic potential in cancer treatment. Thalidomide is also used in the treatment of inflammatory skin disorders and has shown promising effect in the treatment of autoimmune disorders and inflammatory bowel disease. Despite thalidomide being a renowned teratogen and neurotoxin, it has been successfully repositioned and FDA approved for the treatment of erythema nodosum leprosum and multiple myeloma under strict control.

Thalidomide Exerts Anti-Inflammatory Effects in Cutaneous Lupus by Inhibiting the IRF4/NF-ҡB and AMPK1/mTOR Pathways

“…CRBN functions as a substrate receptor for the cullin-4-containing E3 ubiquitin ligase complex CUL4–RBX1–DDB1 (CRL4A) and is responsible for the recruitment of substrates for degradation by the ubiquitin-proteasome pathway. IMiDs bind to CRBN and alter the substrate specificity of CRL4 CRBN blocking the degradation of proteins involved in angiogenesis, tumoral activity and inflammation [ 54 , 55 ] but also inducing teratogenicity [ 56 ].…”

Thalidomide for the Management of Gastrointestinal Bleeding in a Palliative Care Setting

“…Nuclear factor kappa B (NFκB) is another pathway implicated in thalidomide action and targets genes such as for interleukin 8, interleukin signal transducer tumor necrosis factor receptor-associated factor 1, and cellular inhibitor of apoptosis protein 2 (IAP2) [77]. The inhibition of NFκB is triggered by downregulation of TNF-α via thalidomide (by targeting cereblon) and also leads to downregulation of other cytokines that promote induction of angiogenesis [72,78]. Thalidomide further facilitates cross talk between pathways of angiogenic signaling (VEGF, PI3/AKT, and NFκB) by mammalian target of rapamycin (mTOR) [72].…”

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

“…Thalidomide has already been repurposed from its original approved use as a morning sickness medication to its present use as a multiple myeloma therapy [ 189 ]. Thalidomide monotherapy in refractory and relapsed patients showed partial response rates of 40% [ 190 ].…”