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Tumor Biology

, Volume 37, Issue 11, pp 15053–15063 | Cite as

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

  • Yang-Yang Dong
  • Yi-Huang Zhuang
  • Wen-Jie Cai
  • Yan Liu
  • Wen-Bing Zou
Original Article

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.

Keywords

Pancreatic cancer NPC-26 Mitochondrion mPTP Gemcitabine 

Notes

Compliance with ethical standards

Conflicts of interests

None

Finance support

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

Supplementary material

13277_2016_5403_MOESM1_ESM.eps (561 kb)
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)

References

  1. 1.
    Costello E, Neoptolemos JP. Pancreatic cancer in 2010: new insights for early intervention and detection. Nat Rev Gastroenterol Hepatol. 2011;8:71–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Ducreux M, Boige V, Malka D. Treatment of advanced pancreatic cancer. Semin Oncol. 2007;34:S25–30.CrossRefPubMedGoogle Scholar
  4. 4.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Blaszkowsky L. Treatment of advanced and metastatic pancreatic cancer. Front Biosci. 1998;3:E214–25.CrossRefPubMedGoogle Scholar
  7. 7.
    Yang Y, Karakhanova S, Hartwig W, D’Haese JG, Philippov PP, Werner J, Bazhin AV (2016) Mitochondria and mitochondrial ros in cancer: Novel targets for anticancer therapy. J Cell PhysiolGoogle Scholar
  8. 8.
    Costantini P, Jacotot E, Decaudin D, Kroemer G. Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst. 2000;92:1042–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002;84:153–66.CrossRefPubMedGoogle Scholar
  10. 10.
    Tsujimoto Y, Shimizu S. Role of the mitochondrial membrane permeability transition in cell death. Apoptosis. 2007;12:835–40.CrossRefPubMedGoogle Scholar
  11. 11.
    Javadov S, Kuznetsov A. Mitochondrial permeability transition and cell death: the role of cyclophilin d. Front Physiol. 2013;4:76.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Madamba SM, Damri KN, Dejean LM, Peixoto PM. Mitochondrial ion channels in cancer transformation. Front Oncol. 2015;5:120.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lu JH, Shi ZF, Xu H. The mitochondrial cyclophilin d/p53 complexation mediates doxorubicin-induced non-apoptotic death of a549 lung cancer cells. Mol Cell Biochem. 2014;389:17–24.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang LY, Wu YL, Gao XH, Guo F. Mitochondrial protein cyclophilin-d-mediated programmed necrosis attributes to berberine-induced cytotoxicity in cultured prostate cancer cells. Biochem Biophys Res Commun. 2014;450:697–703.CrossRefPubMedGoogle Scholar
  15. 15.
    Minjie S, Defei H, Zhimin H, Weiding W, Yuhua Z. Targeting pancreatic cancer cells by a novel hydroxamate-based histone deacetylase (hdac) inhibitor st-3595. Tumour Biol. 2015;36:9015–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Chen MB, Jiang Q, Liu YY, Zhang Y, He BS, Wei MX, JW L, Ji Y, PH L. C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving amp-activated protein kinase-p53 signaling. Carcinogenesis. 2015;36:1061–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Wolpaw AJ, Shimada K, Skouta R, Welsch ME, Akavia UD, Pe'er D, Shaik F, JC B, BR S. Modulatory profiling identifies mechanisms of small molecule-induced cell death. Proc Natl Acad Sci U S A. 2011;108:E771–80.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bu HQ, Liu DL, Wei WT, Chen L, Huang H, Li Y, Cui JH. Oridonin induces apoptosis in sw1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 mapk. Oncol Rep. 2014;31:975–82.PubMedGoogle Scholar
  19. 19.
    Chen B, Xu M, Zhang H, Xu MZ, Wang XJ, Tang QH, Tang JY. The antipancreatic cancer activity of osi-027, a potent and selective inhibitor of mtorc1 and mtorc2. DNA Cell Biol. 2015;34:610–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Min H, Xu M, Chen ZR, Zhou JD, Huang M, Zheng K, Zou XP. Bortezomib induces protective autophagy through amp-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemother Pharmacol. 2014;74:167–76.CrossRefPubMedGoogle Scholar
  21. 21.
    Huo HZ, Wang B, Qin J, Guo SY, Liu WY, Gu Y. Amp-activated protein kinase (ampk)/ulk1-dependent autophagic pathway contributes to c6 ceramide-induced cytotoxic effects in cultured colorectal cancer ht-29 cells. Mol Cell Biochem. 2013;378:171–81.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhen YF, Wang GD, Zhu LQ, Tan SP, Zhang FY, Zhou XZ, Wang XD. P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol. 2014;229:1475–83.CrossRefPubMedGoogle Scholar
  23. 23.
    Chang CC, Liao YS, Lin YL, Chen RM. Nitric oxide protects osteoblasts from oxidative stress-induced apoptotic insults via a mitochondria-dependent mechanism. J Orthop Res. 2006;24:1917–25.CrossRefPubMedGoogle Scholar
  24. 24.
    Meeran SM, Katiyar S, Katiyar SK. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicol Appl Pharmacol. 2008;229:33–43.CrossRefPubMedGoogle Scholar
  25. 25.
    Qiu Y, Yu T, Wang W, Pan K, Shi D, Sun H. Curcumin-induced melanoma cell death is associated with mitochondrial permeability transition pore (mptp) opening. Biochem Biophys Res Commun. 2014;448:15–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang CL, Wu LJ, Tashiro S, Onodera S, Ikejima T. Oridonin induced a375-s2 cell apoptosis via bax-regulated caspase pathway activation, dependent on the cytochrome c/caspase-9 apoptosome. J Asian Nat Prod Res. 2004;6:127–38.CrossRefPubMedGoogle Scholar
  27. 27.
    Sullivan PG, Thompson MB, Scheff SW. Cyclosporin a attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol. 1999;160:226–34.CrossRefPubMedGoogle Scholar
  28. 28.
    Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin a acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-d at a different site from cyclosporin a. J Biol Chem. 2002;277:34793–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhou C, Chen Z, Lu X, Wu H, Yang Q, Xu D 2015 Icaritin activates jnk-dependent mptp necrosis pathway in colorectal cancer cells. Tumour BiolGoogle Scholar
  30. 30.
    Ying L, Chunxia Y, Wei L. Inhibition of ovarian cancer cell growth by a novel tak1 inhibitor lytak1. Cancer Chemother Pharmacol. 2015;76:641–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Kai S, Lu JH, Hui PP, Zhao H. Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent. Biochem Biophys Res Commun. 2014;452:768–74.CrossRefPubMedGoogle Scholar
  32. 32.
    Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Salem AF, Tsirigos A, Lamb R, Sneddon S, Hulit J, Howell A, Lisanti MP. Mitochondria "fuel" breast cancer metabolism: fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells. Cell Cycle. 2012;11:4390–401.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Shoshan-Barmatz V, Ben-Hail D, Admoni L, Krelin Y, Tripathi SS. The mitochondrial voltage-dependent anion channel 1 in tumor cells. Biochim Biophys Acta. 2015;1848:2547–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Gesto DS, Cerqueira NM, Fernandes PA, Ramos MJ. Gemcitabine: a critical nucleoside for cancer therapy. Curr Med Chem. 2012;19:1076–87.CrossRefPubMedGoogle Scholar
  35. 35.
    Plunkett W, Huang P, YZ X, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995;22:3–10.PubMedGoogle Scholar
  36. 36.
    Chen SH, Li DL, Yang F, Wu Z, Zhao YY, Jiang Y. Gemcitabine-induced pancreatic cancer cell death is associated with mst1/cyclophilin d mitochondrial complexation. Biochimie. 2014;103:71–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Yang-Yang Dong
    • 1
  • Yi-Huang Zhuang
    • 1
  • Wen-Jie Cai
    • 1
  • Yan Liu
    • 1
  • Wen-Bing Zou
    • 1
  1. 1.Department of Surgical OncologyFirst Hospital of Quanzhou Affiliated to Fujian Medical UniversityQuanzhouChina

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