Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer

Ganji Purnachandra Nagaraju, Batoul Farran, Matthew Farren, Gayathri Chalikonda, Christina Wu, Gregory B. Lesinski, Bassel F. El-Rayes

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms. Method: Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models. Results: Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N-acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS-mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts. Conclusion: Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.

Original languageEnglish (US)
Pages (from-to)3360-3371
Number of pages12
JournalCancer
Volume126
Issue number14
DOIs
StatePublished - Jul 15 2020
Externally publishedYes

Keywords

  • angiogenesis
  • colorectal cancer
  • DNA damage
  • napabucasin (BBI 608)
  • reactive oxygen species (ROS)
  • STAT3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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