Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor

  • Authors:
    • Gaku Matsumoto
    • Mariko Muta
    • Kazuo Umezawa
    • Tomoyoshi Suzuki
    • Keizo Misumi
    • Koji Tsuruta
    • Atsutake Okamoto
    • Masakazu Toi
  • View Affiliations

  • Published online on: November 1, 2005     https://doi.org/10.3892/ijo.27.5.1247
  • Pages: 1247-1255
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The effects of the nuclear factor (NF)-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-α were evaluated in PK-8 pancreatic cancer cells. NF-κB was activated by TNF-α; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-α markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (ΔΨm) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of ΔΨm suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-α was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-α may be a promising treatment for pancreatic cancer.

Related Articles

Journal Cover

November 2005
Volume 27 Issue 5

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

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Matsumoto, G., Muta, M., Umezawa, K., Suzuki, T., Misumi, K., Tsuruta, K. ... Toi, M. (2005). Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor. International Journal of Oncology, 27, 1247-1255. https://doi.org/10.3892/ijo.27.5.1247
MLA
Matsumoto, G., Muta, M., Umezawa, K., Suzuki, T., Misumi, K., Tsuruta, K., Okamoto, A., Toi, M."Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor". International Journal of Oncology 27.5 (2005): 1247-1255.
Chicago
Matsumoto, G., Muta, M., Umezawa, K., Suzuki, T., Misumi, K., Tsuruta, K., Okamoto, A., Toi, M."Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor". International Journal of Oncology 27, no. 5 (2005): 1247-1255. https://doi.org/10.3892/ijo.27.5.1247