TY - JOUR
T1 - Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells
AU - Sharma, Anup
AU - Vatapalli, Rajita
AU - Abdelfatah, Eihab
AU - McMahon, K. Wyatt
AU - Kerner, Zachary
AU - Guzzetta, Angela A.
AU - Singh, Jasvinder
AU - Zahnow, Cynthia
AU - Baylin, Stephen B.
AU - Yerram, Sashidhar
AU - Hu, Yue
AU - Azad, Nilofer
AU - Ahuja, Nita
N1 - Funding Information:
There is a competing interest: Dr. Ahuja receives research grant funding from Astex Inc. and the Van Andel Research Institute. She has licensed methylation biomarkers to Cepheid. Dr. Ahuja also has served as consultant to Johnson and Johnson. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2017 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/4
Y1 - 2017/4
N2 - 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).
AB - 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).
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U2 - 10.1371/journal.pone.0176139
DO - 10.1371/journal.pone.0176139
M3 - Article
C2 - 28445481
AN - SCOPUS:85018274190
SN - 1932-6203
VL - 12
JO - PloS one
JF - PloS one
IS - 4
M1 - e0176139
ER -