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

Anup Sharma, Rajita Vatapalli, Eihab Abdelfatah, K. Wyatt McMahon, Zachary Kerner, Angela A. Guzzetta, Jasvinder Singh, Cynthia Zahnow, Stephen B. Baylin, Sashidhar Yerram, Yue Hu, Nilofer Azad, Nita Ahuja

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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).

Original languageEnglish (US)
Article numbere0176139
JournalPloS one
Volume12
Issue number4
DOIs
StatePublished - Apr 2017
Externally publishedYes

Fingerprint

irinotecan
Chemotherapy
colorectal neoplasms
drug therapy
Colorectal Neoplasms
Cells
Heterografts
Drug Therapy
Cytidine
Oncology
DNA
Cell adhesion
cell lines
Cell growth
Testing
Cell Line
Agar
Tumors
Assays
Repair

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. / Sharma, Anup; Vatapalli, Rajita; Abdelfatah, Eihab; McMahon, K. Wyatt; Kerner, Zachary; Guzzetta, Angela A.; Singh, Jasvinder; Zahnow, Cynthia; Baylin, Stephen B.; Yerram, Sashidhar; Hu, Yue; Azad, Nilofer; Ahuja, Nita.

In: PloS one, Vol. 12, No. 4, e0176139, 04.2017.

Research output: Contribution to journalArticle

Sharma, A, Vatapalli, R, Abdelfatah, E, McMahon, KW, Kerner, Z, Guzzetta, AA, Singh, J, Zahnow, C, Baylin, SB, Yerram, S, Hu, Y, Azad, N & Ahuja, N 2017, 'Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells', PloS one, vol. 12, no. 4, e0176139. https://doi.org/10.1371/journal.pone.0176139
Sharma, Anup ; Vatapalli, Rajita ; Abdelfatah, Eihab ; McMahon, K. Wyatt ; Kerner, Zachary ; Guzzetta, Angela A. ; Singh, Jasvinder ; Zahnow, Cynthia ; Baylin, Stephen B. ; Yerram, Sashidhar ; Hu, Yue ; Azad, Nilofer ; Ahuja, Nita. / Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. In: PloS one. 2017 ; Vol. 12, No. 4.
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