Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

• Published in: PloS one 2017-04, Vol.12 (4), p.e0176139-e0176139
• Main Authors: Sharma, Anup, Vatapalli, Rajita, Abdelfatah, Eihab, Wyatt McMahon, K, Kerner, Zachary, A Guzzetta, Angela, Singh, Jasvinder, Zahnow, Cynthia, B Baylin, Stephen, Yerram, Sashidhar, Hu, Yue, Azad, Nilofer, Ahuja, Nita
• Format: Article
• Language: English
• Subjects: Agar; Animals; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Azacitidine - therapeutic use; Azacitidine - toxicity; Bioinformatics; Biology and Life Sciences; Biotechnology; Caco-2 Cells; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Camptothecin - toxicity; Cancer; Cancer cells; Cancer therapies; Care and treatment; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA repair; DNA Repair - drug effects; Dosage and administration; Drug dosages; Epigenetics; Gene expression; Gene Expression - drug effects; Gene Expression Profiling; Genomes; HCT116 Cells; Health aspects; Humans; Irinotecan; Long Interspersed Nucleotide Elements - genetics; Medical research; Medicine; Medicine and Health Sciences; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Oncology; Priming; Research and Analysis Methods; Sharma, Anup; Studies; Surgery; Synergism; Tumors; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0176139

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment. For irinotecan (IRI), growth diminished by 16-62 fold as assessed, by both proliferation (IC50) and anchorage independent cell growth soft agar assays. Treatment of resistant HCT116 cell line along with in-vivo, for CRC line xenografts, AZA plus IRI again exhibits this synergistic response with significant improvement in survival and tumor regression in the mice. Genome-wide expression correlates changes in pathways for cell adhesion and DNA repair with the above responses. A Phase 1/2 clinical trial testing this concept is already underway testing the clinical efficacy of this concept in IRI resistant, metastatic CRC (NCT01896856).