Open Access

Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins

  • Authors:
    • Paksiree Saranaruk
    • Ryusho Kariya
    • Gunya Sittithumcharee
    • Parichart Boueroy
    • Thidarut Boonmars
    • Kanlayanee Sawanyawisuth
    • Chaisiri Wongkham
    • Sopit Wongkham
    • Seiji Okada
    • Kulthida Vaeteewoottacharn
  • View Affiliations

  • Published online on: January 29, 2020     https://doi.org/10.3892/ijmm.2020.4482
  • Pages: 1005-1016
  • Copyright: © Saranaruk et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cholangiocarcinoma (CCA) is a cancer of biliary epithelium. Late diagnosis and resistance to conventional chemotherapy are the major obstacles in CCA treatment. Increased expression of anti‑apoptotic proteins are observed in CCA, which might confer chemoresistance. Thus, modulations of anti‑apoptotic proteins leading to apoptotic induction is the focus of this study. Chromomycin A3 (CMA3), an anthraquinone glycoside‑mithramycin A analog, was selected. CMA3 strongly binds to GC‑rich regions in DNA, where specificity protein 1 (Sp1), a common transcription factor of apoptosis‑related proteins, is preferentially bounded. The effects of CMA3 on anti‑proliferation, cell cycle arrest and apoptosis induction in CCA cells were demonstrated by MTT assay, flow cytometry and western blot analysis. The results showed CMA3 suppressed cell proliferation in vitro in the nM range. At low doses, CMA3 inhibited cell cycle progression at S phase, while it promoted caspase‑dependent apoptosis at higher doses. CMA3 induced effects of apoptosis were through the suppression of Sp1‑related anti‑apoptotic proteins, FADD‑like IL‑1β‑converting enzyme‑inhibitory protein, myeloid cell leukemia‑1, X‑linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis and survivin. The anti‑CCA effects of CMA3 were confirmed in the xenograft mouse model. CMA3 retarded xenograft tumor growth. Taken together, CMA3 induced apoptosis in CCA cells by diminishing the Sp1‑related anti‑apoptotic proteins is demonstrated. CMA3 might be useful as a chemosensitizing agent.
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April-2020
Volume 45 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Saranaruk P, Kariya R, Sittithumcharee G, Boueroy P, Boonmars T, Sawanyawisuth K, Wongkham C, Wongkham S, Okada S, Vaeteewoottacharn K, Vaeteewoottacharn K, et al: Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins. Int J Mol Med 45: 1005-1016, 2020
APA
Saranaruk, P., Kariya, R., Sittithumcharee, G., Boueroy, P., Boonmars, T., Sawanyawisuth, K. ... Vaeteewoottacharn, K. (2020). Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins. International Journal of Molecular Medicine, 45, 1005-1016. https://doi.org/10.3892/ijmm.2020.4482
MLA
Saranaruk, P., Kariya, R., Sittithumcharee, G., Boueroy, P., Boonmars, T., Sawanyawisuth, K., Wongkham, C., Wongkham, S., Okada, S., Vaeteewoottacharn, K."Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins". International Journal of Molecular Medicine 45.4 (2020): 1005-1016.
Chicago
Saranaruk, P., Kariya, R., Sittithumcharee, G., Boueroy, P., Boonmars, T., Sawanyawisuth, K., Wongkham, C., Wongkham, S., Okada, S., Vaeteewoottacharn, K."Chromomycin A3 suppresses cholangiocarcinoma growth by induction of S phase cell cycle arrest and suppression of Sp1‑related anti‑apoptotic proteins". International Journal of Molecular Medicine 45, no. 4 (2020): 1005-1016. https://doi.org/10.3892/ijmm.2020.4482