Molecular Therapy of Cancer

Molecular Therapy of Cancer

prof. Ing. Jiří Neužil, CSc.

prof. Ing. Jiří Neužil, CSc. — Project head

About us

The project is focused on the development of new anti-cancer agents that selectively counteract malignancies.

Research Objectives:

  • To design, prepare and test effective anti-cancer agents, especially with regard to the selective killing of malignant cells.
  • To analyse and understand the molecular biology and the resistance of cancer stem cells towards apoptosis.
  • To propose and verify effective therapeutic strategies which can be used in clinical medicine to minimize cancer relapses.

 

In collaboration with Australian research group (Mitochondria, Apoptosis and Cancer Research Group, Griffith University, Southport, Qld, Australia), the laboratory focuses on the design and development of novel anti-cancer agents, in particular vitamin E analogues, that are efficient and selective for malignant cells. The researchers are especially interested in the molecular mechanism of apoptosis caused by such agents, which includes pathways of mitochondrial destabilisation. They have defined and characterized the group of ‘mitocans’, small molecules relaying their anti-cancer activity via mitochondria. These agents are particularly intriguing from the translational point of view, since it is now clear that tumours are extremely heterogeneous in their mutations, even within different regions of the same tumour. Therefore, mitochondria may present an invariant target that can be utilized for cancer therapy.

A particular focus of the group is on mitocans from the group of vitamin E analogues, represented by the redox-silent compound α-tocopheryl succinate (α-TOS). This agent exerts high apoptogenic activity towards a variety of cancer cell lines while being non-toxic to normal cells. This in vitro pro-apoptotic activity is matched by its anti-cancer activity in mouse models of tumours, which the group has shown for colorectal, breast and mesothelioma tumours. This finding endows α-TOS with substantial translational spin and/or makes it a lead compound for the design of more efficient agents.

In the attempt to characterize the pathway(s) regulating apoptotic signalling in cancer cells triggered by α-TOS, the researchers discovered a new target of anti-cancer drugs, the mitochondrial complex II (CII). Interestingly, they found that α-TOS (and similar compounds) interacts with the proximal and distal ubiquinone (UbQ)-binding site of CII, thereby replacing UbQ in CII. CII, by means of its succinate dehydrogenase (SDH) activity, converts succinate to fumarate as a component of the tricarboxylic acid (TCA) cycle. Electrons released from this reaction are normally intercepted by UbQ and donated to CIII of the electron transport chain (ETC), part of oxidative phosphorylation. In case UbQ is replaced by α-TOS or similar compounds, the electrons recombine with molecular oxygen and cause generation of superoxide, triggering the apoptosis signalling cascade. Since genes coding for the subunit of CII mutate only exceptionally, the complex presents a very intriguing target for anti-cancer drugs.

In the attempt to increase the apoptogenic activity of α-TOS, the agent was modified by tagging with the cationic triphenylphosphonium (TPP) group, which causes the accumulation of the agent (mitochondrially targeted vitamin E succinate, MitoVES) at the interface of the mitochondrial inner membrane and the mitochondrial matrix, enhancing the apoptogenic activity of the parental compound by 1–2 orders of magnitude. Importantly, this increase in toxicity towards cancer cells did not compromise the selectivity of the agent for malignant cells. The approach of the group to cancer therapy by tagging anti-cancer agents with lipophilic cations epitomised by TPP presents a novel paradigm of efficient cancer therapy. The group is further pursuing this line of research to synthesize novel, more efficient anti-cancer agents targeting mitochondria. In particular, they plan to initiate translational research, whereby delivering their novel agents to the clinic. If successful, this may change the landscape of current and future cancer therapeutic modalities potentially leading to efficient cancer treatment.

News

Events

Publications

2017

Bezawork-Geleta, A., Rohlena, J., Dong, L., Pacak, K., Neuzil, J. Mitochondrial complex II: At the Crossroads. Trends in Biochemical Sciences, 42(4): 312-325, 2017. doi: 10.1016/j.tibs.2017.01.003. ISSN 0968-0004.

Blecha, J., Novais, S. M., Rohlenova, K., Novotna, E., Lettlova, S., Schmitt, S., Zischka, H., Neuzil, J., Rohlena, J. Antioxidant defense in quiescent cells determines selectivity of electron transport chain inhibitor-induced cell death. Free Radical Biology and Medicine, 112: 253-266, 2017. doi: 10.1016/j.freeradbiomed.2017.07.033. ISSN 0891-5849.

Cuyas, E., Fernandez-Arroyo, S., Verdura, S., Garcia, R. A-F., Stursa, J., Werner, L., Blanco-Gonzalez, E., Montes-Bayon, M., Joven, J., Viollet, B., Neuzil, J., Menendez, J. A. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene, [ahead of print], 2017. doi: 10.1038/onc.2017.367. eISSN 1476-5594.

Dong LF, Kovarova J, Bajzikova M, Bezawork-Geleta A, Svec D, Endaya B, Sachaphibulkij K, Coelho AR, Sebkova N, Ruzickova A, Tan AS, Kluckova K, Judasova K, Zamecnikova K, Rychtarcikova Z, Gopalan V, Andera L, Sobol M, Yan B, Pattnaik B, Bhatraju N, Truksa J, Stopka P, Hozak P, Lam AK, Sedlacek R, Oliveira PJ, Kubista M, Agrawal A, Dvorakova-Hortova K, Rohlena J, Berridge MV, Neuzil J. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. Elife. 2017 Feb 15;6. pii: e22187.

Grimolizzi, F., Monaco, F., Leoni, F., Bracci, M., Staffolani, S., Bersaglieri, C., Gaetani, S., Valentino, M., Amati, M., Rubini, C., Saccucci, F., Neuzil, J., Tomasetti, M., Santarelli, L. Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression. Scienticif Reports, 7: 15277, 2017. doi: 10.1038/s41598-017-15475-6. eISSN 2045-2322.

Rohlenova, K., Sachaphibulkij, K., Stursa, J., Bezawork-Geleta, A., Blecha, J., Endaya, B., Werner, L., Cerny, J., Zobalova, R., Goodwin, J., Spacek, T., Alisadeh, E., Yan, B., Nguyen, M., Vondrusova, M., Sobol, M., Jezek, P., Hozak, P., Truksa, J., Rohlena, J., Dong, L., Neuzil, J. Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2-high breast cancer. Antioxidants & Redox Signaling, 26(2): 84-103, 2017. doi: 10.1089/ars.2016.6677. ISSN 1557-7716.

Rychtarcikova, Z., Lettlova, S., Tomkova, V., Korenkova, V., Langerova, L., Simonova, E., Zjablovskaja, P., Alberich-Jorda, M., Neuzil, J., Truksa, J. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget, 8: 6376-6398, 2017. doi: 10.18632/oncotarget.14093. ISSN: 1949-2553.

Tomasetti, M., Amati, M., Neuzil, J., Santarelli, L. Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy. Lung Cancer, 107: 65-72, 2017. doi: 10.1016/j.lungcan.2016.05.023. ISSN 1872-8332.

Tomasetti, M., Lee, W., Santarelli, L., Neuzil, J. Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy. Experimental and Molecular Medicine, 49(1): e285, 2017. doi: 10.1038/emm.2016.153. eISSN 2092-6413.

2016

Berridge, M. V., McConnell, M. J., Grasso, C., Bajzikova, M., Kovarova, J., Neuzil, J. Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. Current Opinion in Genetics and Development, 38: 75-82, 2016. doi: 10.1016/j.gde.2016.04.003. ISSN 1879-0380.

Bezawork-Geleta, A., Dong, L., Rohlena, J., Neuzil, J. The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells. Journal of Biological Chemistry, 291: 21414-21420, 2016. doi: 10.1074/jbc.C116.755017. eISSN 1083-351X

Boukalova, S., Stursa, J., Werner, L., Ezrova, Z., Cerny, J., Bezawork-Geleta, A., Pecinova, A., Dong, L., Drahota, Z., Neuzil, J. Mitochondrial Targeting of Metformin Enhances Its Activity against Pancreatic Cancer. Molecular Cancer Therapeutics, 15(12): 2875-2886, 2016. doi: 10.1158/1535-7163.MCT-15-1021. ISSN 1535-7163.

Endaya, B., Cavanagh, B., Alowaidi, F., Walker, T., de Pennington, N., Ng, J. M. A., Lam, P. Y. P., Mackay-Sim, A., Neuzil, J., Meedeniya, A. C. B. Isolating dividing neural and brain tumour cells for gene expression profiling. Journal of Neuroscience Methods, 257: 121-133, 2016. doi: 10.1016/j.jneumeth.2015.09.020. ISSN 0165-0270.

Endaya, B. B., Lam, P. Y. P., Meedeniya, A. C. B., Neuzil, J. Transcriptional profiling of dividing tumor cells detects intratumor heterogeneity linked to cell proliferation in a brain tumor model. Molecular Oncology, 10(1): 126-137, 2016. doi: 10.1016/j.molonc.2015.09.001. ISSN 1574-7891.

Klanova, M., Andera, L., Brazina, J., Svadlenka, J., Benesova, S., Soukup, J., Prukova, D., Vejmelkova, D., Jaksa, R., Helman, K., Vockova, P., Lateckova, L., Molinsky, J., Maswabi, B. C., Alam, M., Kodet, R., Pytlik, R., Trneny, M., Klener, P. Targeting of BCL2 family proteins with ABT-199 and homoharringtonine reveals BCL2- and MCL1-dependent subgroups of diffuse large B-cell lymphoma. Clinical Cancer Research, 22(5): 1138-1149, 2016. doi: 10.1158/1078-0432.CCR-15-1191. ISSN 1078-0432.

Moudra, A., Hubackova, S., Machalova, V., Vancurova, M., Bartek, J., Reinis, M., Hodny, Z., Jonasova, A. Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine. OncoImmunology, 5(10): e1183860, 2016. doi: 10.1080/2162402X.2016.1183860. eISSN 2162-402X.

Murtaza, M., Shan, J., Matigian, N., Todorovic, M., Cook, A. L., Ravishankar, S., Dong, L. F., Neuzil, J., Silburn, P., Mackay-Sim, A., Mellick, G. D., Wood, S. A. Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease. PLoS ONE, 11(4): e0154544, 2016. doi: 10.1371/journal.pone.0154544. ISSN 1932-6203.

Rohlenova, K., Neuzil, J., Rohlena, J. The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria. Biological Chemistry, 397(7): 607-615, 2016. doi: 10.1515/hsz-2016-0130. ISSN 1437-4315.

Tomasetti, M., Monaco, F., Manzella, N., Rohlena, J., Rohlenova, K., Staffolani, S., Gaetani, S., Ciarapica, V., Amati, M., Bracci, M., Valentino, M., Goodwin, J., Nguyen, M., Truksa, J., Sobol, M., Hozak, P., Dong, L. F., Santarelli, L., Neuzil, J. MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma. Oncotarget, 7(24): 36338-36352, 2016. doi: 10.18632/oncotarget.8916. ISSN 1949-2553.

Tomasetti, M., Amati, M., Santarelli, L., Neuzil, J. MicroRNA in metabolic re-programming and their role in tumorigenesis. International Journal of Molecular Sciences, 17(5): 754, 2016. doi: 10.3390/ijms17050754. ISSN 1422-0067.

Vanova, K., Boukalova, S., Gbelcova, H., Muchova, L., Neuzil, J., Gurlich, R., Ruml, T., Vitek, L. Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells. BMC Cancer, 16: 309, 2016. doi: 10.1186/s12885-016-2343-9. ISSN 1471-2407.

2015

Berridge, M. V., Dong, L., Neuzil, J. Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer. Cancer Research, 75: 3203-3208, 2015. doi: 10.1158/0008-5472.CAN-15-0859. ISSN 1538-7445.

Khera, A., Dong, L. F., Holland, O., Vanderlelie, J., Pasdar, E. A., Neuzil, J., Perkins, A. V. Selenium supplementation induces mitochondrial biogenesis in trophoblasts. Placenta, 36(8): 863-869, 2015. doi: 10.1016/j.placenta.2015.06.010.

Kluckova, K., Sticha, M., Cerny, J., Mracek, T., Dong, L., Drahota, Z., Gottlieb, E., Neuzil, J., Rohlena, J. Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. Cell Death & Disease, 6: e1749, 2015. doi: 10.1038/cddis.2015.110. ISSN 2041-4889.

Koudelka, S., Turanek Knotigova, P., Masek, J., Prochazka, L., Lukac, R., Miller, A. D., Neuzil, J., Turanek, J. Liposomal delivery systems for anti-cancer analogues of vitamin E. Journal of Controlled Release, 207: 59-69, 2015. doi: 10.1016/j.jconrel.2015.04.003. ISSN 0168-3659.

Pasdar, E. A., Smits, M., Stapelberg, M., Bajzikova, M., Stantic, M., Goodwin, J., Yan, B., Stursa, J., Kovarova, J., Sachaphibulkij, K., Bezawork-Geleta, A., Sobol, M., Filimonenko, A., Tomasetti, M., Zobalova, R., Hozak, P., Dong, L. F., Neuzil, J. Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents. PLoS ONE, 10(5): e0119549, 2015. doi: 10.1371/journal.pone.0119549. ISSN 1932-6203. Correction, 2016.

Santarelli, L., Staffolani, S., Strafella, E., Nocchi, L., Manzella, N., Grossi, P., Bracci, M., Pignotti, E., Alleva, R., Borghi, B., Pompili, C., Sabbatini, A., Rubini, C., Zuccatosta, L., Bichisecchi, E., Valentino, M., Horwood, K., Comar, M., Bovensi, M., Dong, L. F., Neuzil, J., Amati, M., Tomasetti, M. Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. Lung Cancer, 90(3): 457-464, 2015. doi: 10.1016/j.lungcan.2015.09.021.

Tan, A. S., Baty, J. W., Dong, L., Bezawork-Geleta, A., Endaya, B., Goodwin, J., Bajzikova, M., Kovarova, J., Peterka, M., Yan, B., Pesdar, E. A., Sobol, M., Filimonenko, A., Stuart, S., Vondrusova, M., Kluckova, K., Sachaphibulkij, K., Rohlena, J., Hozak, P., Truksa, J., Eccles, D., Haupt, L. M., Griffiths, L. R., Neuzil, J., Berridge, M. V. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metabolism, 21(1): 81-94, 2015. doi: 10.1016/j.cmet.2014.12.003. ISSN 1550-4131.

Tomasetti, M., Santarelli, L., Alleva, R., Dong, L. F., Neuzil, J. Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer. Current Medicinal Chemistry, 22(5): 552-568, 2015. doi: 10.2174/0929867321666140915142219. ISSN 0929-8673.

Truksa, J., Dong, L., Rohlena, J., Stursa, J., Vondrusova, M., Goodwin, J., Nguyen, M., Kluckova, K., Rychtarcikova, Z., Lettlova, S., Spacilova, J., Stapelberg, M., Zoratti, M., Neuzil, J. Mitochondrially targeted vitamin E succinate modulates expression of mitochondrial DNA transcripts and mitochondrial biogenesis. Antioxidants & Redox Signaling, 22(11): 883-900, 2015. doi: 10.1089/ars.2013.5594. ISSN 1523-0864.

Vondrusova, M., Bezawork-Geleta, A., Sachaphibulkij, K., Truksa, J., Neuzil, J. The effect of mitochondrially targeted anticancer agents on mitochondrial (super)complexes. Mitochondrial Medicine, 1265: 195-208, 2015. doi: 10.1007/978-1-4939-2288-8_15. ISSN 1064-3745.

Yan, B., Stantic, M., Zobalova, R., Bezawork-Geleta, A., Stapelberg, M., Stursa, J., Prokopova, K., Dong, L. F., Neuzil, J. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner. BMC Cancer, 15: 401, 2015. doi: 10.1186/s12885-015-1394-7. ISSN 1471-2407.

2014


Hwang, M. S., Rohlena, J., Dong, L. F., Neuzil, J., Grimm, S. Powerhouse down: Complex II dissociation in the respiratory chain. Mitochondrion Part A, 19: 20-28, 2014. doi: 10.1016/j.mito.2014.06.001. ISSN 1567-7249.

Kovarova, J., Bajzikova, M., Vondrusova, M., Stursa, J., Goodwin, J., Nguyen, M., Zobalova, R., Pesdar, E. A., Truksa, J., Tomasetti, M., Dong, L. F., Neuzil, J. Mitochondrial targeting of alpha-tocopheryl succinate enhances its anti-mesothelioma efficacy. Redox Reports, 19(1): 16-25, 2014. doi: 10.1179/1351000213Y.0000000064.

Stapelberg, M., Zobalova, R., Nguyen, M. N., Walker, T., Stantic, M., Goodwin, J., Pasdar, E. A., Thai, T., Prokopova, K., Yan, B., Hall, S., de Pennington, N., Thomas, S. R., Grant, G., Stursa, J., Bajzikova, M., Meedeniya, A. C. B., Truksa, J., Ralph, S. J., Ansorge, O., Dong, L. F., Neuzil, J. Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans. Free Radical Biology and Medicine, 67: 41-50, 2014. doi: 10.1016/j.freeradbiomed.2013.10.003.

Tomasetti, M., Nocchi, L., Staffolani, S., Manzella, N., Amati, M., Goodwin, J., Kluckova, K., Nguyen, M., Strafella, E., Bajzikova, M., Peterka, M., Lettlova, S., Truksa, J., Lee, W., Dong, L. F., Santarelli, L., Neuzil, J. MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function. Antioxidants & Redox Signaling, 21(15): 2109-2125, 2014. doi: 10.1089/ars.2013.5215. ISSN 1523-0864.

Tomasetti, M., Neuzil, J., Dong, L. F. MicroRNAs as regulators of mitochondrial function: Role in cancer suppression. Biochimica et Biophysica Acta - General Subjects, 1840(4): 1441-1453, 2014. doi: 10.1016/j.bbagen.2013.09.002.

Tomasetti, M., Santarelli, L., Neuzil, J., Dong, L. MicroRNA regulation of cancer metabolism: role in tumour suppression. Mitochondrion Part A, 19: 29-38, 2014. doi: 10.1016/j.mito.2014.06.004. ISSN 1567-7249.

2013

Kluckova, K., Bezawork-Geleta, A., Rohlena, J., Dong, L., Neuzil, J. Mitochondrial complex II, a novel target for anti-cancer agents. Biochimica Et Biophysica Acta-Bioenergetics, 1827(5): 552-564, 2013. doi: 10.1016/j.bbabio.2012.10.015. ISSN 0005-2728.

Kovarova, N., Mracek, T., Nuskova, H., Holzerova, E., Vrbacky, M., Pecina, P., Hejzlarova, K., Kluckova, K., Rohlena, J., Neuzil, J., Houstek, J. High Molecular Weight Forms of Mammalian Respiratory Chain Complex II. PLoS ONE, 8(8): e71869, 2013. doi: 10.1371/journal.pone.0071869. ISSN 1932-6203.

Moreno-Sanchez, R., Hernandez-Esquivel, L., Rivero-Segura, N. A., Marin-Hernandez, A., Neuzil, J., Ralph, S. J., Rodriguez-Enriquez, S. Reactive oxygen species are generated by the respiratory complex II - evidence for lack of contribution of the reverse electron flow in complex I. FEBS Journal, 280(3): 927-938, 2013. doi: 10.1111/febs.12086. ISSN 1742-464X.

Neuzil, J., Dong, L. F., Rohlena, J., Truksa, J., Ralph, S. J. Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion, 13(3): 199-208, 2013. doi: 10.1016/j.mito.2012.07.112. ISSN 1567-7249.

Prochazka, L., Koudelka, S., Dong L. F., Stursa, J., Goodwin, J., Neca, J., Slavik, J., Ciganek, M., Masek, J., Kluckova, K., Nguyen, M., Turanek, J., Neuzil, J. Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to alpha-tocopheryl succinate. Apoptosis, 18(3): 286-299, 2013. doi: 10.1007/s10495-012-0795-1. ISSN 1360-8185.

Rohlena, J., Dong, L. F., Neuzil, J. Targeting the Mitochondrial Electron Transport Chain Complexes for the Induction of Apoptosis and Cancer Treatment. Current Pharmaceutical Biotechnology, 14(3): 377-389, 2013. doi: 10.2174/1389201011314030011. ISSN 1389-2010.

Team

prof. Ing. Jiří Neužil, CSc.

prof. Ing.
Jiří Neužil, CSc.

Head of Group Molecular Therapy of Tumors

jiri.neuzil@ibt.cas.cz
+420325873796

RNDr.
Ladislav Anděra, CSc.

ladislav.andera@ibt.cas.cz
+420325873796

Mgr.
Jakub Rohlena, Ph.D.

jakub.rohlena@ibt.cas.cz
+420325873795

Mgr.
Štěpána Boukalová, Ph.D.

stepana.boukalova@ibt.cas.cz
+420325873795

Mgr.
Renata Zobalová, Ph.D.

renata.zobalova@ibt.cas.cz
+420325873721

Mgr.
Jaromíra Kovářová, Ph.D.

jaromira.kovarova@ibt.cas.cz
+420325873721

Ing.
Kateřina Váňová, Ph.D.

katerina.vanova@ibt.cas.cz
+420325873795

RNDr.
Soňa Hubáčková, Ph.D.

sona.hubackova@ibt.cas.cz
+420325873795

RNDr.
Luděk Štěpánek, Ph.D.

ludek.stepanek@ibt.cas.cz
+420325873721

Mgr.
Eva Budinská, Ph.D.

eva.budinska@ibt.cas.cz
+420325873796