Mitochondrial induction as a potential radio-sensitizer in lung cancer cells - a short report
Tóm tắt
Lung cancer is the leading cause of cancer death. Radiation therapy plays a key role in its treatment. Ionizing radiation induces cell death through chromosomal aberrations, which trigger mitotic catastrophe and apoptosis. However, many lung cancer patients show resistance to radiation. Dichloroacetate (DCA) is a small molecule that can promote mitochondrial activation by increasing the influx of pyruvate. Here, we tested whether DCA may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity. We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Mitochondrial induction by DCA may serve as a radio-sensitizer in non-small cell lung cancer.
Tài liệu tham khảo
R. Siegel, C. DeSantis, K. Virgo, K. Stein, A. Mariotto, T. Smith, D. Cooper, T. Gansler, C. Lerro, S. Fedewa, C. Lin, C. Leach, R.S. Cannady, H. Cho, S. Scoppa, M. Hachey, R. Kirch, A. Jemal, E. Ward, Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin. 62(4), 220–241 (2012)
Q. Wu, Y.F. Chen, J. Fu, Q.H. You, S.M. Wang, X. Huang, X.J. Feng, S.H. Zhang, Short hairpin RNA-mediated down-regulation of CENP-A attenuates the aggressive phenotype of lung adenocarcinoma cells. Cell. Oncol. 37(6), 399–407 (2014)
A. Koren, H. Motaln, T. Cufer, Lung cancer stem cells: a biological and clinical perspective. Cell. Oncol. 36(4), 265–275 (2013)
N. Peled, M.W. Wynes, N. Ikeda, T. Ohira, K. Yoshida, J. Qian, M. Ilouze, R. Brenner, Y. Kato, C. Mascaux, F.R. Hirsch, Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cell. Oncol. 36(4), 277–288 (2013)
M.V. Graham, J.A. Purdy, B. Emami, W. Harms, W. Bosch, M.A. Lockett, C.A. Perez, Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int. J. Radiat. Oncol. Biol. Phys. 45(2), 323–329 (1999)
H. Vakifahmetoglu, M. Olsson, B. Zhivotovsky, Death through a tragedy: mitotic catastrophe. Cell Death Differ. 15(7), 1153–1162 (2008)
J. Thoms, R.G. Bristow, DNA repair targeting and radiotherapy: a focus on the therapeutic ratio. Semin. Radiat. Oncol. 20(4), 217–222 (2010)
C. Coleman, Beneficial liaisons: radiobiology meets cellular and molecular biology. Radiother Oncol: J. Eur. Soc. Ther. Radiol. Oncol. 28(1), 1–15 (1993)
T. Yamamori, H. Yasui, M. Yamazumi, Y. Wada, Y. Nakamura, H. Nakamura, O. Inanami, Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. Free Radic. Biol. Med. 53(2), 260–270 (2012)
I. Szumiel, Ionising radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int J Radiat Biol. 1–55 (2014)
B.A. Rupnow, S.J. Knox, The role of radiation-induced apoptosis as a determinant of tumor responses to radiation therapy. Apoptosis 4(2), 115–143 (1999)
R.A. Cairns, I.S. Harris, T.W. Mak, Regulation of cancer cell metabolism. Nat. Rev. Cancer 11(2), 85–95 (2011)
E.D. Michelakis, L. Webster, J.R. Mackey, Dichloroacetate (DCA) as a potential metabolic targeting therapy for cancer. Br. J. Cancer 99(7), 989–994 (2008)
X. Wang, S. Peralta, C.T. Moraes, Mitochondrial alterations during carcinogenesis: a review of metabolic transformation and targets for anticancer treatments. Adv. Cancer Res. 119, 127–160 (2013)
J. Atkinson, A.A. Kapralov, N. Yanamala, Y.Y. Tyurina, A.A. Amoscato, L. Pearce, J. Peterson, Z. Huang, J. Jiang, A.K. Samhan-Arias, A. Maeda, W. Feng, K. Wasserloos, N.A. Belikova, V.A. Tyurin, H. Wang, J. Fletcher, Y. Wang, I.I. Vlasova, J. Klein-Seetharaman, D.A. Stoyanovsky, H. Bayir, B.R. Pitt, M.W. Epperly, J.S. Greenberger, V.E. Kagan, A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death. Nat. Commun. 2, 497 (2011)
S.H. Kim, Y.H. Yoo, J.H. Lee, J.W. Park, Mitochondrial NADP(+)-dependent isocitrate dehydrogenase knockdown inhibits tumorigenicity of melanoma cells. Biochem. Biophys. Res. Commun. 451(2), 246–251 (2014)
Z. Tatarkova, S. Kuka, M. Petras, P. Racay, J. Lehotsky, D. Dobrota, P. Kaplan, Why mitochondria are excellent targets for cancer therapy. Klin. Onkol. 25(6), 421–426 (2013)
S. Bonnet, S.L. Archer, J. Allalunis-Turner, A. Haromy, C. Beaulieu, R. Thompson, C.T. Lee, G.D. Lopaschuk, L. Puttagunta, G. Harry, K. Hashimoto, C.J. Porter, M.A. Andrade, B. Thebaud, E.D. Michelakis, A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1), 37–51 (2007)
N.A. Franken, H.M. Rodermond, J. Stap, J. Haveman, C. van Bree, Clonogenic assay of cells in vitro. Nat. Protoc. 1(5), 2315–2319 (2006)
B.K. Slinker, The statistics of synergism. J. Mol. Cell. Cardiol. 30(4), 723–731 (1998)
W. Cao, S. Yacoub, K.T. Shiverick, K. Namiki, Y. Sakai, S. Porvasnik, C. Urbanek, C.J. Rosser, Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68(11), 1223–1231 (2008)
F. Zwicker, A. Kirsner, P. Peschke, F. Roeder, J. Debus, P.E. Huber, K.J. Weber, Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo. Strahlenther. Onkol. 189(8), 684–692 (2013)
I. Papandreou, R.A. Cairns, L. Fontana, A.L. Lim, N.C. Denko, HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3(3), 187–197 (2006)
S. Lee, M.J. Lim, M.H. Kim, C.H. Yu, Y.S. Yun, J. Ahn, J.Y. Song, An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses. Free Radic. Biol. Med. 53(4), 807–816 (2012)
S.J. Chmura, H.J. Mauceri, S. Advani, R. Heimann, M.A. Beckett, E. Nodzenski, J. Quintans, D.W. Kufe, R.R. Weichselbaum, Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation. Cancer Res. 57(19), 4340–4347 (1997)
V. Bhardwaj, Y. Zhan, M.A. Cortez, K.K. Ang, D. Molkentine, A. Munshi, U. Raju, R. Komaki, J.V. Heymach, J. Welsh, C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. J. Thorac. Oncol. 7(8), 1211–1217 (2012)
E.J. Bernhard, G. Kao, A.D. Cox, S.M. Sebti, A.D. Hamilton, R.J. Muschel, W.G. McKenna, The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Cancer Res. 56(8), 1727–1730 (1996)
H.J. Boeckman, K.S. Trego, J.J. Turchi, Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of nonhomologous end joining. Mol. Cancer Res. 3(5), 277–285 (2005)
N. Balaban, J. Moni, M. Shannon, L. Dang, E. Murphy, T. Goldkorn, The effect of ionizing radiation on signal transduction: antibodies to EGF receptor sensitize A431 cells to radiation. Biochim. Biophys. Acta 1314(1–2), 147–156 (1996)