Synergistic Anticancer Effects of JQ-1 and Doxorubicin via MYC Downregulation and Apoptosis Induction

Synergistic Anticancer Effects of JQ-1 and Doxorubicin via MYC Downregulation and Apoptosis Induction

Alvin Sherman Library

Aggressive cancers are particularly challenging due to their rapid growth, ability to adapt, and resistance to single therapies. Combination therapies or a multipronged approach can increase tumor cell killing and limit the development of drug resistance. The potential of combining conventional chemotherapy with targeted therapies was investigated. To determine the best drug combinations, viability assays using an 8 x 8 dose response matrix format (checkerboard) with small-step serial dilutions of cytotoxic and targeted drugs was performed. The resulting viability data, as determined by MTS assay, was analyzed using the web application SynergyFinder. The results indicated that the combined drug treatment of the bromodomain inhibitor, JQ-1, and the cytotoxic agent, doxorubicin (DOX) gave an overall very high synergy score of 11.1 when tested on the pediatric glioblastoma cell line, SJGBM-2. Synergy was also observed, although not to the same extent, in the neuroblastoma cell line, SK-N-Be2C, and the triple negative breast cancer cell line, MDA-MB-231. Western blot analysis revealed that the drug combination induced robust caspase-7 activation and PARP cleavage, indicating apoptosis in all 3 cell lines. Furthermore, while JQ1 decreased MYC/NMYC oncogene expression somewhat, the combination of DOX and JQ1 virtually eliminated the expression of the oncogenes. MYC oncogenes are transcription factors involved in the expression of genes necessary for cell proliferation, apoptosis avoidance, metabolic reprogramming, and angiogenesis. The study identified a drug combination that was effective in multiple cancer cell lines, and preliminary results suggest that its efficacy may be due to the downregulation of MYC family members.