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The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo

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Tumor Biology

Abstract

The development of novel anti-pancreatic cancer agents is extremely important. Here, we investigated the anti-pancreatic cancer activity by NPC-26, a novel mitochondrion interfering compound. We showed that NPC-26 was anti-proliferative and cytotoxic to human pancreatic cancer cells, possibly via inducing caspase-9-dependent cell apoptosis. Pharmacological inhibition or shRNA-mediated silence of caspase-9 attenuated NPC-26-induced pancreatic cancer cell death and apoptosis. Further, NPC-26 treatment led to mitochondrial permeability transition pore (mPTP) opening in the cancer cells, which was evidenced by mitochondrial depolarization, ANT-1(adenine nucleotide translocator-1)-Cyp-D (cyclophilin-D) association and oxidative phosphorylation disturbance. mPTP blockers (cyclosporin and sanglifehrin A) or shRNA-mediated knockdown of key mPTP components (Cyp-D and ANT-1) dramatically attenuated NPC-26-induced pancreatic cancer cell apoptosis. Importantly, we showed that NPC-26, at a low concentration, potentiated gemcitabine-induced mPTP opening and subsequent pancreatic cancer cell apoptosis. In vivo, NPC-26 intraperitoneal injection significantly suppressed the growth of PANC-1 xenograft tumors in nude mice. Meanwhile, NPC-26 sensitized gemcitabine-mediated anti-pancreatic cancer activity in vivo. In summary, the results of this study suggest that NPC-26, alone or together with gemcitabine, potently inhibits pancreatic cancer cells possibly via disrupting mitochondrion.

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Authors and Affiliations

  1. Department of Surgical Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian, 362000, China

    Yang-Yang Dong, Yi-Huang Zhuang, Wen-Jie Cai, Yan Liu & Wen-Bing Zou

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  1. Yang-Yang Dong
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  2. Yi-Huang Zhuang
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  3. Wen-Jie Cai
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  4. Yan Liu
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  5. Wen-Bing Zou
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Correspondence to Yang-Yang Dong.

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Scientific research fund of the First Hospital of Quanzhou Affiliated to Fujian Medical University (20140085).

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Supplementary Figure 1

HepG2 hepatocellular carcinoma cells and HT-29 colorectal cancer cells were either left untreated (“Ctrl”) or treated with NPC-26 (10 μM) for applied time, cell survival, and apoptosis were analyzed by MTT assay (a) and ssDNA ELISA assay (b), respectively. Data were expressed as mean ± SD, experiments were repeated three times. n = 5 for each assay. *p < 0.05 vs. “Ctrl” group. (EPS 561 kb)

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Dong, YY., Zhuang, YH., Cai, WJ. et al. The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo. Tumor Biol. 37, 15053–15063 (2016). https://doi.org/10.1007/s13277-016-5403-5

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  • DOI: https://doi.org/10.1007/s13277-016-5403-5

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