Apoptosis in tumor cells subjected to the combined action of hyperthermia and irradiation: a study of the molecular mechanisms and targets

«Radiation and Risk», 2018, vol. 27, no. 2, pp.62-75

DOI: 10.21870/0131-3878-2018-27-2-62-75

Authors

Kabakov A.E. – Head of Lab., C. Sc., Biol. A. Tsyb MRRC, Obninsk, Russia. Contacts: 4 Korolyov str., Obninsk, Kaluga region, Russia, 249036. Tel.: +7 (484) 399-32-97-7188; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Kudryavtsev V.A. – Researcher. A. Tsyb MRRC, Obninsk, Russia.
Khokhlova A.V. – Jun. Researcher. A. Tsyb MRRC, Obninsk, Russia.
Makarova Yu.M. – Researcher. A. Tsyb MRRC, Obninsk, Russia.
Lebedeva T.V. – Lead. Researcher, C. Sc., Biol. A. Tsyb MRRC, Obninsk, Russia.

Abstract

In the present work we investigated the molecular nature of the radiosensitizing action of hyperthermia on various cancer cells. Tumor cell lines derived from human carcinomas (HeLa, MCF-7), fibrosarcoma (HT 1080) and T-lymphoma (Jurkat) were here explored. The cell cultures were exposed to hyperthermic conditions (42-44 °С) and/or irradiated with γ-photons (2-6 Gy); then such parameters were assessed as the intensity and type of cell death, clonogenicity, amounts of DNA double strand breaks and their repair dynamics, localization of heat shock proteins etc. We showed that (1) the hyperthermia-induced enhancement of post-radiation cell death is mainly due to stimulation of caspase-dependent apoptosis, (2) triggering of such apoptotic mechanism appears to result in a default of the cellular response to radiation damage to genome, (3) expression and distribution of heat shock proteins HSP90, HSP70 and HSP27 can be the important determinants defining the further fate (survival or “suicide”) of the malignant cell experienced hyperthermia and radiation exposure. It is here discussed that such factors as the heat stress response, level of aggregated cellular protein and functional activities of HSPs can substantially influence on the effectiveness of radiosensitization of tumors by heating. New approaches and targets are considered for the enhancement of radiosensitizing action of hyperthermia on cancer cells.

Key words
Radiosensitization, γ-radiation, γH2AX foci, DNA repair, heat stress, caspase, heat shock proteins, proteotoxicity, protein denaturation, tumors, radiobiological effects, radiation therapy.

References

1. Kurpeshev O.K. Possibilities and prospects of use of hyperthermia in medicine. Klinicheskaya meditsina – Clinical Medicine, 1996, no. 1, pp. 14-16. (In Russian).

2. Kurpeshev O.K., Andreev V.G., Pankratov V.A., Gulidov I.A., Orlova A.V. Comparative results of con-servative chemoradiation and thermochemoradiation therapy of locally expansive larynx cancer. Voprosi onkologii – Questions of Oncology, 2014, vol. 60, no. 5, pp. 602-606. (In Russian).

3. Datta N.R., Ordonez S.G., Gaipl U.S., Paulides M.M., Crezee H., Gellermann J., Marder D., Puric E., Bodis S. Local hyperthermia combined with radiotherapy and/or chemotherapy: recent advances and promises for the future. Cancer Treat. Rev., 2015, vol. 41, no. 9, pp. 742-753.

4. Kurpeshev O.K., van der Zee J. Local/regional hyperthermia to malignant tumors: techniques, thermometry, equipment. Meditsinskaya radiologiya i radiatsionnaya bezopasnost’ – Medical Radiology and Radiation Safety, 2017, no. 5, pp. 53-63. (In Russian).

5. Ohguri T. Current status of clinical evidence for electromagnetic hyperthermia on prospective trials. Thermal Med., 2015, vol. 31, no. 2, pp. 5-12.

6. Kurpeshev O.K., Ragulin Yu.A., Mozerov S.A., Orlova A.V., Lebedeva T.V. Possibilities of local hyperthermia for treatment of patients with edema forms of mammary gland cancer. Voprosi onkologii – Questions of Oncology, 2016, no. 5, pp. 680-687. (In Russian).

7. Kurpeshev O.K. Correlations between radiosensitizing and damaging effects of hyperthermia on normal and tumor tissues (an experimental and clinical study): Dr. med. sci. diss. Obninsk, 1989. (In Russian).

8. Hyperthermic oncology from bench to bedside. Eds.: S. Kokura, T. Yoshikawa, T. Ohnishi. Springer, 2016. 444 p.

9. Kabakov A.E., Gabai V.L. Cell death and survival assays. Methods Mol. Biol., 2018, vol. 1709, pp. 107-127.

10. Sharma A., Singh K., Almasan A. Histone H2AX phosphorylation: a marker for DNA damage. Methods Mol. Biol., 2012, vol. 920, pp. 613-626.

11. Kudryavtsev V.A., Makarova Yu.M., Kabakov A.E. Thermosensitization of tumor cells with inhibitors of chaperone activity and expression. Biomeditsinskaya khimiya – Biomedical Chemistry, 2012, vol. 58, no. 6, pp. 662-672. (In Russian).

12. Kabakov A.E., Gabai V.L. Protein aggregation as primary and characteristic cell reaction to various stresses. Experientia, 1993, vol. 49, no. 8, pp. 706-713.

13. Kabakov A.E., Gabai V.L. Stress-induced insolubilization of certain proteins in ascites tumor cells. Arch. Biochem. Biophys., 1994, vol. 309, no. 2, pp. 247-253.

14. Schmitt C.A. Cellular senescence and cancer treatment. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 2007, vol. 1775, pp. 5-20.

15. O’Callaghan-Sunol C., Gabai V.L. Involvement of heat shock proteins in protection of tumor cells from genotoxic stresses. A chapter in: Heat shock proteins in cancer. Eds.: S.K. Calderwood, M.Y. Sherman, D.R. Ciocca. Springer, 2007. pp. 169-189.

16. Koff J.L., Ramachandiran S., Bernal-Mizrachi L. A time to kill: targeting apoptosis in cancer. Int. J. Mol. Sci., 2015, vol. 16, pp. 2942-2955.

17. Balcer-Kubiczek E.K. Apoptosis in radiation therapy: a double-edged sword. Exp. Oncol., 2012, vol. 34, no. 3, pp. 277-285.

18. Pandita T.K., Pandita S., Bhaumik S.R. Molecular parameters of hyperthermia for radiosensitization. Crit. Rev. Eukaryot. Gene Expr., 2009, vol. 19, no. 3, pp. 235-251.

19. Van den Tempel N., Laffeber C., Odijk H., van Cappelen W.A., van Rhoon G.C., Franckena M., Kanaar R. The effect of thermal dose on hyperthermia-mediated inhibition of DNA repair through homologous recombination. Oncotarget, 2017. doi: 10.18632/oncotarget.17861.

20. Takahashi A., Mori E., Nakagawa Y., Kajihara A., Kirita T., Pittman D.L., Hasegawa M., Ohnishi T. Homologous recombination preferentially repairs heat-induced DNA double-strand breaks in mammalian cells. Int. J. Hyperthermia, 2017. doi: 10.1080/02656736.2016.1252989.

21. Van Oorschot B., Granata G., Di Franco S., Ten Cate R., Rodermond H.M., Todaro M., Medema J.P., Franken N.A. Targeting DNA double strand break repair with hyperthermia and DNA-PKcs inhibition to enhance the effect of radiation treatment. Oncotarget, 2016, vol. 7, no. 40, pp. 65504-65513.

22. Kennedy D., Jager R., Mosser D.D., Samali A. Regulation of apoptosis by heat shock proteins. IUBMB Life, 2014, vol. 66, no. 5, pp. 327-338.

23. Kaprin A.D., Galkin V.N., Zhavoronkov L.P., Ivanov V.K., Ivanov S.A., Romanko Yu.S. Synthesis of basic and applied research is the basis of obtaining high-quality findings and translating them into clinical practice. Radiatsiya i risk – Radiation and Risk, 2017, vol. 26, no. 2, pp. 26-40. (In Russian).

Full-text article (in Russian)