Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells

  • Authors:
    • Lisa M. Greene
    • Derek P. Nolan
    • Daniel Regan-Komito
    • Giuseppe Campiani
    • D. Clive Williams
    • Daniela M. Zisterer
  • View Affiliations

  • Published online on: June 25, 2013     https://doi.org/10.3892/ijo.2013.1989
  • Pages: 927-935
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The pyrrolo-1,5-benzoxazepines (PBOXs) are a novel group of selective apoptotic agents displaying promising therapeutic potential in both ex vivo chemotherapy-refractory patient samples and in vivo murine carcinoma models. In this report, we present novel data concerning the induction of autophagy by the PBOXs in adenocarcinoma-derived colon cancer cells. Autophagy is a lysosome-dependent degradative pathway recently associated with chemotherapy. However, whether autophagy facilitates cell survival in response to chemotherapy or contributes to chemotherapy-induced cell death is highly controversial. Autophagy was identified by enhanced expression of LC3B-II, an autophagosome marker, an increase in the formation of acridine orange-stained cells, indicative of increased vesicle formation and electron microscopic confirmation of autophagic structures. The vacuolar H+ ATPase inhibitor bafilomycin-A1 (BAF-A1) inhibited vesicle formation and enhanced the apoptotic potential of PBOX-6. These findings suggest a cytoprotective role of autophagy in these cells following prolonged exposure to PBOX-6. Furthermore, BAF-A1 and PBOX-6 interactions were determined to be synergistic and caspase-dependent. Potentiation of PBOX-6-induced apoptosis by BAF-A1 was associated with a decrease in the levels of the anti-apoptotic protein, Mcl-1. The data provide evidence that autophagy functions as a survival mechanism in colon cancer cells to PBOX-6-induced apoptosis and a rationale for the use of autophagy inhibitors to further enhance PBOX‑6‑induced apoptosis in colon cancer.
View Figures
View References

Related Articles

Journal Cover

September 2013
Volume 43 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Greene LM, Nolan DP, Regan-Komito D, Campiani G, Williams DC and Zisterer DM: Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells. Int J Oncol 43: 927-935, 2013.
APA
Greene, L.M., Nolan, D.P., Regan-Komito, D., Campiani, G., Williams, D.C., & Zisterer, D.M. (2013). Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells. International Journal of Oncology, 43, 927-935. https://doi.org/10.3892/ijo.2013.1989
MLA
Greene, L. M., Nolan, D. P., Regan-Komito, D., Campiani, G., Williams, D. C., Zisterer, D. M."Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells". International Journal of Oncology 43.3 (2013): 927-935.
Chicago
Greene, L. M., Nolan, D. P., Regan-Komito, D., Campiani, G., Williams, D. C., Zisterer, D. M."Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells". International Journal of Oncology 43, no. 3 (2013): 927-935. https://doi.org/10.3892/ijo.2013.1989