Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma

• Type of Material: Article
• Authors: Pilar de la Puente, Washington University; Feda Azab, Washington University; Barbara Muz, Washington University; Micah Luderer, Washington University; Jack Arbiser, Emory University; Abdel Kareem Azab, Washington University
• Language: English
• Date: 2016-07-01
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Informa UK Limited, trading as Taylor & Francis Group
• Final Published Version (URL): http://dx.doi.org/10.3109/10428194.2015.1099645
• Title of Journal or Parent Work: Leukemia & Lymphoma
• ISSN: 1042-8194
• Volume: 57
• Issue: 7
• Start Page: 1677
• End Page: 1686
• Keywords: drug resistance; Life Sciences & Biomedicine; hypoxia; multiple myeloma; EXPRESSION; ACTIVATION; PROTEIN-KINASE; CELL-LINES; CANCER; Tris DBA; Oncology; Hematology; TUMOR PROGRESSION; PROMOTES DISSEMINATION; SRC-FAMILY KINASES; Science & Technology; INHIBITOR; Src; SIGNAL-TRANSDUCTION
• Research Categories: Health Sciences, Oncology; Chemistry, Radiation

Abstract

Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.