Prague Med. Rep. 2014, 115, 104-119

https://doi.org/10.14712/23362936.2014.41

Targeting Mitochondria for Cancer Treatment – Two Types of Mitochondrial Dysfunction

Jiří Pokorný1, Jan Pokorný2, Jitka Kobilková3, Anna Jandová1, Jan Vrba4, Jan Vrba, Jr.5

1Institute of Photonics and Electronics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
2Institute of Physics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
3Department of Obstetrics and Gynaecology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
4Faculty of Electrical Engineering, Czech Technical University in Prague, Prague, Czech Republic
5Faculty of Biomedical Engineering, Czech Technical University in Prague, Kladno, Czech Republic

Received July 1, 2014
Accepted November 18, 2014

References

1. Beloussov, L. V. (2012) Morphogenesis as a macroscopic self-organizing process. Biosystems 109, 262–279. <https://doi.org/10.1016/j.biosystems.2012.05.003>
2. Bonnet, S., Archer, S. L., Allalunis-Turner, J., Haromy, A., Beaulieu, C., Thompson, R., Lee, C. T., Lopaschuk, G. D., Puttagunta, L., Bonnet, S., Harry, G., Hashimoto, K., Porter, C. J., Andrade, M. A., Thebaud, B., Michelakis, E. D. (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51. <https://doi.org/10.1016/j.ccr.2006.10.020>
3. Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D., Pavlides, S., Pestell, R. G., Chiavarina, B., Frank, P. G., Flomenberg, N., Howell, A., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2010a) Ketones and lactate “fuel” tumor growth and metastasis. Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 9, 3506–3514. <https://doi.org/10.4161/cc.9.17.12731> <PubMed>
4. Bonuccelli, G., Whitaker-Menezes, D., Castello-Cros, R., Pavlides, S., Pestell, R. G., Fatatis, A., Witkiewicz, A. K., Vander Heiden, M. G., Migneco, G., Chiavarina, B., Frank, P. G., Capozza, F., Flomenberg, N., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2010b) The reverse Warburg effect. Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle 9, 1960–1971. <https://doi.org/10.4161/cc.9.10.11601>
5. Chen, L. B. (1988) Mitochondrial membrane potential in living cells. Annu. Rev. Cell Biol. 4, 155–181. <https://doi.org/10.1146/annurev.cb.04.110188.001103>
6. Chernet, B. T., Levin, M. (2014) Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range. Oncotarget 5, 3287–3306. <https://doi.org/10.18632/oncotarget.1935> <PubMed>
7. Chiavarina, B., Whitaker-Menezes, D., Migneco, G., Martinez-Outschoorn, U. E., Pavlides, S., Howell, A., Tanowitz, H. B., Casimiro, M. C., Wang, C., Pestell, R. G., Grieshaber, P., Caro, J., Sotgia, F., Lisanti, M. P. (2010) HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells. Autophagy drives compartment-specific oncogenesis. Cell Cycle 9, 3534–3551. <https://doi.org/10.4161/cc.9.17.12908> <PubMed>
8. Fröhlich, H. (1968a) Bose condensation of strongly excited longitudinal electric modes. Phys. Lett. A 26, 402–403. <https://doi.org/10.1016/0375-9601(68)90242-9>
9. Fröhlich, H. (1968b) Long-range coherence and energy storage in biological systems. Int. J. Quantum Chem. II, 641–649. <https://doi.org/10.1002/qua.560020505>
10. Fröhlich, H. (1969) Quantum mechanical concepts in biology. In: Theoretical Physics and Biology, ed. Marois, M., pp. 13–22, North Holland, Amsterdam (Proc. 1st Int. Conf. Theor. Phys. Biol., Versailles, 1967).
11. Fröhlich, H. (1973) Collective behaviour of non-linearly coupled oscillating fields (with applications to biological systems). J. Collect. Phenom. 1, 101–109.
12. Fröhlich, H. (1978) Coherent electric vibrations in biological systems and cancer problem. IEEE Trans. MTT 26, 613–617. <https://doi.org/10.1109/TMTT.1978.1129446>
13. Fröhlich, H. (1980) The biological effects of microwaves and related questions. Adv. Electronics Electron Phys. 53, 85–152. <https://doi.org/10.1016/S0065-2539(08)60259-0>
14. Goldstein, S., Korczack, L. B. (1981) Status of mitochondria in living human fibroblasts during growth and senescence in vitro: Use of the laser dye rhodamine 123. J. Cell Biol. 91, 392–398. <https://doi.org/10.1083/jcb.91.2.392> <PubMed>
15. Heerdt, B. G., Houston, M. A., Wilson, A. J., Augenlicht, L. H. (2003) The intrinsic mitochondrial membrane potential (ΔΨm) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis. Cancer Res. 63, 6311–6319.
16. Heerdt, B. G., Houston, M. A., Augenlicht, L. H. (2006) Growth properties of colonic tumor cells are a function of the intrinsic mitochondrial membrane potential. Cancer Res. 66, 1591–1596. <https://doi.org/10.1158/0008-5472.CAN-05-2717>
17. Jandová, A., Laurová, L., Novotná, J., Škoda, V. (1969a) The level of the fifth isoenzyme LDH in the blood serum in precancerous endometrium patients. Cesk. Gynekol. 34, 402. (in Czech)
18. Jandová, A., Škoda, V., Lavrová, L. (1969b) La frequence d‘isozyme LDH dans le serum sanguin constatee‚ chez les femmes souffrant de cancer de la vulve. C. R. Soc. Fr. Gyncol. 39, 418–419.
19. Jandová, A., Miluničová, A., Škoda, V. (1970) Relation of isoenzyme LDH to hematological values in gynecological carcinoma. Transfúze 4, 91–92. (in Czech)
20. Jandová, A., Kubátová, A., Macků, F., Novotná, J., Pezlarová, A. (1971) LDH activity in blood serum and tumorous tissue in ovarial cancer patients. Cesk. Gynekol. 36, 549–550. (in Czech)
21. Jandová, A., Hurych, J., Pokorný, J., Čoček, A., Trojan, S., Nedbalová, M., Dohnalová, A. (2001) Effects of sinusoidal magnetic field on adherence inhibition of leukocytes. Electro Magnetobiol. 20, 397–413. <https://doi.org/10.1081/JBC-100108578>
22. Jandová, A., Pokorný, J., Kobilková, J., Janoušek, M., Mašata, J., Trojan, S., Nedbalová, M., Dohnalová, A., Beková, A., Slavík, V., Čoček, A., Sanitrák, J. (2009) Cell-mediated immunity in cervical cancer evolution. Electromagn. Biol. Med. 28, 1–14. <https://doi.org/10.1080/15368370802708868>
23. Johnson, L. V., Summerhayes, I. C., Chen, L. B. (1982) Deceased uptake and retention of rhodamine 123 by mitochondria in feline sarcoma virus-transformed mink cells. Cell 28, 7–14. <https://doi.org/10.1016/0092-8674(82)90369-5>
24. Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Serlivanov, V. A., Mackay, G., van der Burg, S. H., Verdegaal, E. M. E., Cascante, M., Shlomi, T., Gottlieb, E., Peeper, D. S. (2013) A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112. <https://doi.org/10.1038/nature12154>
25. Klingenberg, M., Rottenberg, H. (1977) Relation between the gradient of the ATP/ADP ratio and the membrane potential across the mitochondrial membrane. Eur. J. Biochem. 73, 125–130. <https://doi.org/10.1111/j.1432-1033.1977.tb11298.x>
26. Ko, Y. H., Lin, Z., Flomenberg, N., Pestell, R. G., Howell, A., Sotgia, F., Lisanti, M. P., Martinez-Outschoorn, U. E. (2011) Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells. Implications for preventing chemotherapy resistance. Cancer Biol. Ther. 12, 1085–1097. <https://doi.org/10.4161/cbt.12.12.18671> <PubMed>
27. Lampidis, T. J., Bernal, S. D., Summerhayes, I. C., Chen, L. B. (1983) Selective toxicity of rhodamine 123 in carcinoma cells in vitro. Cancer Res. 43, 716–720.
28. Levin, M. (2012) Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning. Biosystems 109, 243–261. <https://doi.org/10.1016/j.biosystems.2012.04.005> <PubMed>
29. Levin, M. (2014) Endogenous bioelectrical networks store non‐genetic patterning information during development and regeneration. J. Physiol. 592, 2295–2305. <https://doi.org/10.1113/jphysiol.2014.271940> <PubMed>
30. Lisanti, M. P., Martinez-Outschoorn, U. E., Chiavarina, B., Pavlides, S., Whitaker-Menezes, D., Tsirigos, A., Witkiewicz, A., Lin, Z., Balliet, R., Howell, A., Sotgia, F. (2010) Understanding the “lethal” drivers of tumor-stroma co-evolution. Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol. Ther. 10, 537–542. <https://doi.org/10.4161/cbt.10.6.13370> <PubMed>
31. Martinez-Outschoorn, U. E., Balliet, R. M., Rivadeneira, D. B., Chiavarina, B., Pavlides, S., Wang, C., Whitaker-Menezes, D., Daumer, K. M., Lin, Z., Witkiewicz, A. K., Flomenberg, N., Howell, A., Pestell, R. G., Knudsen, E. S., Sotgia, F., Lisanti, M. P. (2010a) Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution. A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 9, 3256–3276.
32. Martinez-Outschoorn, U. E., Trimmer, C., Lin, Z., Whitaker-Menezes, D., Chiavarina, B., Zhou, J., Wang, C., Pavlides, S., Martinez-Cantarin, M. P., Cappozza, F., Witkiewicz, A. K., Flomenberg, N., Howell, A., Pestell, R. G., Caro, J., Lisanti, M. P., Sotgia, F. (2010b) Autophagy in cancer associated fibroblasts promotes tumor cell survival. Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 9, 3515–3533. <https://doi.org/10.4161/cc.9.17.12928> <PubMed>
33. Martinez-Outschoorn, U. E., Lin, Z., Ko, Y. H., Goldberg, A. F., Flomenberg, N., Wang, C., Pavlides, S., Pestell, R. G., Howell, A., Sotgia, F., Lisanti, M. P. (2011) Understanding the metabolic basis of drug resistance. Therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 10, 2521–2528. <https://doi.org/10.4161/cc.10.15.16584> <PubMed>
34. Migneco, G., Whitaker-Menezes, D., Chiavarina, B., Castello-Cros, R. C., Pavlides, S., Pestell, R. G., Fatatis, A., Flomenberg, N., Tsirigos, A., Howell, A., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2010) Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis. Evidence for stromal-epithelial metabolic coupling. Cell Cycle 9, 2412–2422. <https://doi.org/10.4161/cc.9.12.11989>
35. Modica-Napolitano, J. S., Aprille, J. R. (1987) Basis for selective cytotoxicity of rhodamine 123. Cancer Res. 47, 4361–4365.
36. Modica-Napolitano, J. S., Weiss, M. J., Chen, L. B., Aprille, J. R. (1984) Rhodamine 123 inhibits bioenergetic function in isolated rat liver mitochondria. Biochem. Biophys. Res. Commun. 118, 717–723. <https://doi.org/10.1016/0006-291X(84)91453-0>
37. Modica-Napolitano, J. S., Steele, G. D. Jr., Chen, L. B. (1989) Aberrant mitochondria in two human colon carcinoma cell lines. Cancer Res. 49, 3369–3373.
38. Modica-Napolitano, J. S., Koya, K., Weisberg, E., Brunelli, B. T., Li, Y., Chen, L. B. (1996) Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077. Cancer Res. 56, 544–550.
39. Nadakavukaren, K. K., Nadakavukaren, J. J., Chen, L. B. (1985) Increased rhodamine 123 uptake by carcinoma cells. Cancer Res. 45, 6093–6099.
40. O’Connor, J. E., Vargas, J. L., Kimler, B. F., Hernandez-Yago, J., Grisolia, S. (1988) Use of rhodamine 123 to investigate alterations in mitochondrial activity in isolated mouse liver mitochondria. Biochem. Biophys. Res. Commun. 151, 568–573. <https://doi.org/10.1016/0006-291X(88)90632-8>
41. Olenchock, B. A., Vander Heiden, M. G. (2013) Pyruvate as a pivot point for oncogene-induced senescence. Cell 153, 1429–1430. <https://doi.org/10.1016/j.cell.2013.06.001> <PubMed>
42. Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2009) Reverse Warburg effect. Aerobic glycolysis and cancer associated fibroblasts and their tumor stroma. Cell Cycle 8, 3984–4001. <https://doi.org/10.4161/cc.8.23.10238>
43. Pavlides, S., Tsirigos, A., Migneco, G., Whitaker-Menezes, D., Chiavarina, B., Flomenberg, N., Frank, P. G., Casimiro, M. C., Wang, C., Pestell, R. G., Martinez-Outschoorn, U. E., Howell, A., Sotgia, F., Lisanti, M. P. (2010a) The autophagic tumor stroma model of cancer. Role of oxidative stress and ketone production in fuelling tumor cell metabolism. Cell Cycle 9, 3485–3505. <https://doi.org/10.4161/cc.9.17.12721> <PubMed>
44. Pavlides, S., Tsirigos, A., Vera, I., Flomenberg, N., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2010b) Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”. A transcriptional informatics analysis with validation. Cell Cycle 9, 2201–2219. <https://doi.org/10.4161/cc.9.11.11848>
45. Pohl, H. A., Braden, T., Robinson, S., Piclardi, J., Pohl, D. G. (1981) Life cycle alterations of the micro-dielectrophoretic effects of cells. J. Biol. Phys. 9, 133–154. <https://doi.org/10.1007/BF01988247>
46. Pokorný, J. (2012) Physical aspects of biological activity and cancer. AIP Adv. 2, 011207-1–11. <https://doi.org/10.1063/1.3699057>
47. Pokorný, J., Hašek, J., Jelínek, F., Šaroch, J., Palán, B. (2001) Electromagnetic activity of yeast cells in the M phase. Electro Magnetobiol. 20, 371–396. <https://doi.org/10.1081/JBC-100108577>
48. Pokorný, J., Vedruccio, C., Cifra, M., Kučera, O. (2011) Cancer physics: diagnostics based on damped cellular elastoelectrical vibrations in microtubules. Eur. Biophys. J. 40, 747–759. <https://doi.org/10.1007/s00249-011-0688-1>
49. Pokorný, J., Cifra, M., Jandová, A., Kučera, O., Šrobár, F., Vrba, J., Vrba, J. Jr., Kobilková, J. (2012a) Targeting mitochondria for cancer treatment. Eur. J. Oncol. 17, 23–36.
50. Pokorný, J., Jandová, A., Nedbalová, M., Jelínek, F., Cifra, M., Kučera, O., Havelka, D., Vrba, J., Vrba, J. Jr., Čoček, A., Kobilková, J. (2012b) Mitochondrial metabolism – Neglected link of cancer transformation and treatment. Prague Med. Rep. 113, 81–94. <https://doi.org/10.14712/23362936.2015.24>
51. Pokorný, J., Foletti, A., Kobilková, J., Jandová, A., Vrba, J., Vrba, J. Jr., Nedbalová, M., Čoček, A., Danani, A., Tuszyński, J. A. (2013a) Biophysical insights into cancer transformation and treatment. Scientific World Journal 2013, doi:10.1155/2013/195028. <https://doi.org/10.1155/2013/195028> <PubMed>
52. Pokorný, J., Pokorný, J., Kobilková, J. (2013b) Postulates on electromagnetic activity in biological systems and cancer. Integr. Biol. (Camb.) 5, 1439–1446. <https://doi.org/10.1039/c3ib40166a>
53. Pokorný, J., Pokorný, J., Kobilková, J., Jandová, A., Vrba, J., Vrba, J. Jr. (2014) Cancer – Pathological breakdown of coherent energy states. Biophys. Rev. Lett. 9, doi:10.1142/S1793048013300077. <https://doi.org/10.1142/S1793048013300077>
54. Reed, P. W. (1979) Ionophores. Methods Enzymol. 55, 435–454. <https://doi.org/10.1016/0076-6879(79)55058-7>
55. Sahu, S., Ghosh, S., Ghosh, B., Aswani, K., Hirata, K., Fujita, D., Bandyopadhyay, A. (2013) Atomic water channel controlling remarkable properties of a single brain microtubule: Correlating single protein to its supramolecular assembly. Biosens. Bioelectron. 47, 141–148. <https://doi.org/10.1016/j.bios.2013.02.050>
56. Seemayer, T. A., Lagacé, R., Schürch, W., Tremblay, G. (1979) Myofibroblasts in the stroma of invasive and metastatic carcinoma. Am. J. Surg. Pathol. 3, 525–533. <https://doi.org/10.1097/00000478-197912000-00005>
57. Škoda, V., Trnková, M., Škramovský, V., Jandová, A., Novotná, J. (1967) Changes of the isoenzyme of lactate dehydrogenase acid (LDH 5) in blood serum in course of cytostatic treatment of gynecological cancer. Cesk. Gynekol. 32, 14–17. (in Czech)
58. Sotgia, F., Whitaker-Menezes, D., Martinez-Outschoorn, U. E., Flomenberg, N., Birbe, R. C., Witkiewicz, A. K., Howell, A., Philp, N. J., Pestell, R. G., Lisanti, M. P. (2012) Mitochondrial metabolism in cancer metastasis. Visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle 11, 1445–1454. <https://doi.org/10.4161/cc.19841> <PubMed>
59. Soto, A. M., Sonnenschein, C. (2011) The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. Bioessays 33, 332–340. <https://doi.org/10.1002/bies.201100025> <PubMed>
60. Sun, R. C., Fadia, M., Dahlstrom, J. E., Parish, C. R., Board, P. G., Blackburn, A. C. (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res. Treat. 120, 253–260. <https://doi.org/10.1007/s10549-009-0435-9>
61. Tyner, K. M., Kopelman, R., Philbert, M. A. (2007) “Nanosized voltmeter” enables cellular-wide electric field mapping. Biophys. J. 93, 1163–1174. <https://doi.org/10.1529/biophysj.106.092452> <PubMed>
62. Vedruccio, C., Meessen, A. (2004) EM cancer detection by means of non-linear resonance interaction. In: Proceedings PIERS, Progress in Electromagnetic Research Symposium, Pisa, Italy, March 28–31, 2004, pp. 909–912.
63. Warburg, O. (1956) On the origin of cancer cells. Science 123, 309–314. <https://doi.org/10.1126/science.123.3191.309>
64. Warburg, O., Posener, K., Negelein, E. (1924) Über den Stoffwechsel der Carcinomzelle. Biochem. Z. 152, 309–344.
65. Witkiewicz, A. K., Whitaker-Menezes, D., Dasgupta, A., Philp, N. J., Lin, Z., Gandara, R., Sneddon, S., Martinez-Outschoorn, U. E., Sotgia, F., Lisanti, M. P. (2012) Using the “reverse Warburg effect” to identify high-risk breast cancer patients. Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle 11, 1108–1117. <https://doi.org/10.4161/cc.11.6.19530> <PubMed>
66. Zarbl, H., Latreille, J., Jolicoeur, P. (1987) Revertants of v-fos-transformed fibroblasts have mutations ion cellular genes essential for transformation by other oncogenes. Cell 51, 357–369. <https://doi.org/10.1016/0092-8674(87)90632-5>
67. Zheng, J. M., Pollack, G. H. (2003) Long-range forces extending from polymer-gel surfaces. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 68, 031408. <https://doi.org/10.1103/PhysRevE.68.031408>
68. Zheng, J. M., Pollack, G. H. (2006) Solute exclusion and potential distribution near hydrophilic surfaces. In: Water and the Cell, eds. Pollack, G. H., Cameron, I., Wheatley, D. N., pp. 165–174, Springer, Dordrecht.
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