Prof. Dr. Bernd Kaina

DNA repair in protection against malignancy, cell death and senescence

DNA repair in the cell protective system

A cell normally has two copies of each gene while germ cells have actually only one copy. Therefore, DNA damage cannot be replaced, as in the case of other cell components, but rather repaired. DNA damage, which has not been repaired, leads to cell death and, ultimately, to mutations in case of cell survival. These mutations have far-reaching consequences for both the cell and organism levels (see Figure). The unrepaired damage to DNA is the starting point for the development of cancer. On a cellular level, DNA repair can be considered the main defence system through which genetic material is protected from harmful exposures.

We analyse the meaning of the different DNA repair pathways in the cells’ protection system with regard to cytotoxicity, genotoxic changes and malignant transformation (cancer) in our projects. We work with cells which show defects in certain DNA repair pathways, or else produce genetic cells as well as in individuals (mice), in which certain repair pathways are strongly expressed or inactivated (knockdown, knockout). In this way, we showed, for instance, that the MGMT repair protein is extremely important for both the cells’ protection system and the organism against alkylating carcinogens. These carcinogens are to be found in food and tobacco smoke. We also showed that a repair system- a mismatch repair- is necessary to convert certain lesions into genotoxic damage. At the same time, this demonstrates that, although DNA repair normally protects, it can also turn out defective and have fatal consequences for the cells.

Kaina B. (2022) Chemische Kanzerogenese, Lehrbuchbeitrag in: Aktories K., Flockerzi V., Förstermann U., Hofmann F., Urban & Fischer Verlag, München, Jena, 13. Auflage, 1030-1056

Kaina B., Beltzig L., Strik H. (2022) Temozolomide - just a radiosensitizer? Front Oncol.https://www.frontiersin.org/articles/10.3389/fonc.2022.912821/full 2022 Jun 16;12:912821. doi: 10.3389/fonc.2022.912821.

Kaina B, Christmann M. (2019) DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas, DNA Repair, 78: 128-141

Dörsam B., Seiwert N., Foersch S., Stroh S., Nagel G., Begaliew D., Diehl E., Kraus A., McKeague M., Minneker V., Roukos V., Reißig S., Waisman A., Moehler M., Stier A., Mangerich A., Dantzer F., Kaina B., Fahrer J. (2018) PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression, Proc Natl Acad Sci U S A, 115(17), 4061-4070

Kaina B. (2017) DNA-Reparatur und Darmkrebs: Wie Escheria coli und Darmzellen sich vor Genotoxinen schützen, Naturwiss. Rundsch., 7, 328-335

Ensminger M., Iloff L., Ebel C., Nikolova T., Kaina B., Löbrich M. (2014) DNA breaks and chromosomal aberrations arise when replication meets base excision repair, J. Cell Sci., 206, 29-43   

Efferth, T., Kaina B. (2007) Chemical carcinogenesis: genotoxic and non-genotoxic mechanisms. In: H. Greim and R. Snyder(edts), Toxicology and risk assessment: a comprehensive introduction, John Wiley & Sons Ltd., pp. 151-179

Christmann M., Tomicic-Christmann M., Roos W., Kaina B. (2003) Mechanisms of human DNA-repair - an update, Toxicology, 193, 3-34

Crosslink repair mechanisms

There are agents that create crosslinks in DNA. These substances are of particular importance for tumor chemotherapy, such as cyclophosphamide used to treat many tumors (including breast cancer). Cells with defects in crosslink repair are highly sensitive to these genotoxic substances and die by programmed cell death (apoptosis). In this project we investigated the mechanisms that lead to cell death starting from DNA crosslinks.

Goldstein M., Roos W., Kaina B. (2008) Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: contribution of DNA replication, transcription inhibition and Chk/p53 signalling, Toxicology and Applied Pharmacology, 229, 20-32

Brozovic A., Fritz G., Christmann M., Zisowsky J., Jaehde U., Osmak M., Kaina B. (2004) Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance, International Journal of Cancer, 112, 974-985

MGMT – a double-edged sword

DNA repair is important not only to the cells’ protection system against UV light, X-radiation and environmental carcinogens but it also plays a role as a “resistance marker” in the tumour therapy. So, the repair protein MGMT is an eminently important resistance marker for cytostatics which have an effect on methylating drugs such as procarbazine, dacarbazine and temozolomide; and on chloroethylating drugs, such as carmustine, nimustine, lomustine and fotemustine.

Many tumours express low levels of MGMT. These tumours are probably very sensitive to the abovementioned cytostatics. We are carrying out experiments on tumour tissue with regard to MGMT activity. Furthermore, we are pursuing the strategy of blocking the MGMT protein through purposefully selected inhibitors, in order to sensitise the tumour for the therapy with alkylating agents. 

Tomaszowski KH, Hellmann N, Ponath V, Takatsu H, Shin HW, Kaina B. (2017) Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases, Scientific Reports, 7(1):13925. doi: 10.1038/s41598-017-14129-x

Christmann M., Kaina B. (2016) MGMT - A critical DNA repair gene target for chemotherapy resistance, in 2nd edition, M.R. Kelley and M.L. Fishel (edts): DNA Repair in Cancer Therapy, Molecular Targets and Clinical Applications, pp. 55-82

Fahrer J., Kaina B. (2013) O6-Methylguanine-DNA methyltransferase (MGMT) in the defense against N-nitroso compounds and colorectal cancer, Carcinogenesishttps://pubmed.ncbi.nlm.nih.gov/23929436/, 34, 2435-2442

Christmann M., Kaina B. (2012) O⁶-Methylguanine-DNA methyltransferase: impact on cancer risk in response to tobacco smoke, Mutation Research, 736, 64-74

Christmann M., Verbeek B., Roos W.P., Kaina B. (2011) O⁶-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry, Biochem. Biophys. Acta, Rev. Cancer, 1816, 179-190

Strik H., Buhk J., Wrede A., Hoffmann A., Bock C., Christmann M., Kaina B. (2008) Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas, Molecular Medicine Reports, 1, 863-867

Wiewrodt D., Nagel G., Dreimüller N., Hundsberger T., Perneczky A., Kaina B. (2008) MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome, International Journal of Cancer, 122, 1391-1399

Kaina B., Christmann M., Naumann S., Roos W. (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair, 6, 1079-1099

Koch D., Hundsberger T., Boor S., Kaina B. (2007) Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma, Journal of  Neuro-Oncology, 82, 85-89

Kaina B., Muhlhausen U., Piee-Staffa A., Christmann M., Garcia Boy R., Rosch F., Schirrmacher R. (2004) Inhibition of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors: comparison with nonconjugated inhibitors and effect on fotemustine and temozolomide-induced cell death, Journal of Pharmacology and Experimental Therapeutics, 311, 585-593

Preuss I., Eberhagen I., Haas S., Eichhorn U., Kaufman M., Beck T., Eibl R., Dall P., Bauknecht T., Dippold W., Hengstler J., Kaina B. (1996) Activity of the DNA repair protein O6-methylguanine-DNA methyltransferase in human tumor and normal tissue, Cancer Detection and Prevention, 20, 130-136

Mechanisms of apoptosis triggered by specific DNA lesions

The DNA damage O⁶-methylguanine not only creates mutations, it is also toxic to the cell. The lesion is induced in the DNA by environmental mutagens as well as by anticancer drugs (e.g. temozolomide) and is not only responsible for tumor development, but also activates the pathway leading to programmed cell death (apoptosis). We investigated in detail the mechanism that leads to apoptosis, starting from O⁶-methylguanine, in mouse and CHO cells, human fibroblasts, lymphocytes, glioblastoma and melanoma cells and were able to show that two rounds of DNA replication and mismatch repair are essential for apoptosis induction. The complex chain of events that leads to the death of tumor cells runs particularly efficiently when the tumor suppressor protein p53 is present (through activation of the ATR/ATM-CHK1/2-HIPK2-p53ser46 axis). MGMT is an important resistance factor. For chloroethylating drugs, p53 does not play an enhancing role, but suppresses apoptosis by simulating DNA repair (through activation of the genes encoding DDBs and XPC).

He Y., Roos W.P., Wu Q., Hofmann T.G., Kaina B. (2019) The SIAH1-HIPK2-p53ser46 damage response pathway is involved in temozolomide -induced glioblastoma cell death, Mol. Cancer Res., 17(5):1129-1141

Kaina, B. (2019) Temotolomide in glioblastoma therapy: role of apoptosis, senescence and autophagy. Comment Strobel et al., Temozolomide and other alkylanting agents in glioblastoma therapy. Biomedicines 2019, 7, 69. Biomedicines, 7(4)

Roos W.P., Frohnapfel L., Quiros S., Ringel F., Kaina B. (2018) XRCC3 contributes to temozolomide resistance of glioblastoma cells by promoting DNA double-strand break repair, Cancer Lett. 424:119-126

Roos, W.P., A.D. Thomas and B. Kaina (2016) DNA damage and the balance between survival and death in cancer biology, Nature Rev. Cancer, 16 (1), 20-33

Roos W., Batista L., Naumann S., Wick W., Weller M., Menck C., Kaina B. (2007) Apoptosis in malignant glioma cells triggered by the temozolomide- induced DNA lesion O6- methylguanine, Oncogene, 26, 186-197

Kaina B., Christmann M., Naumann S., Roos W. (2007) MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair, 6, 1079-1099

Batista L., Roos W., Christmann M., Menck C., Kaina B. (2007) Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2 and DNA double-strand breaks, Cancer Research, 67, 11886-11895

Cellular senescence triggered by DNA lesions

DNA damage also induces aging at the cellular level, called cellular senescence. Senescent cells do not divide and can survive in this dormant state for long periods of time. They are characterized by secretion of inflammatory cytokines and have high levels of inherent ROS production and DNA damage. We could show that the critical DNA damage O⁶-methylguanine induces more senescence than apoptosis in glioblastoma cells; senescence is thus an important endpoint caused by environmental carcinogens and cytostatics. The elimination of senescent cells can be accomplished by specific substances: the senolytics. We have identified senolytics in the glioblastoma model and proposed them for supportive tumor therapy. These include fisetin and artesunate, both natural substances with therapeutic potential.

Beltzig L., Christmann M., Kaina B. (2022) Abrogation of cellular senescence induced by temozolomide in glioblastoma cells: search for senolytica, Cells, 11(16):2588

Beltzig L., Schwarzenbach C., Leukel P., Frauenknecht K.B.M., Sommer C., Tancredi A., Hegi M.E., Christmann M., Kaina B. (2022) Senescence is the main trait induced by temozolomide in glioblastoma cells, Cancers, 14(9), 2233pp

Beltzig L., Stratenwerth B., Kaina B. (2021) Accumulation of temozolomide-induced apoptosis, senescence and DNA damage by metronomic dose schedule. A proof-of-principle study with glioblastoma cells, Cancers (Basel), 13(24):6287

Stratenwerth B., Geisen S.M., He Y., Beltzig L., Sturla S., Kaina B. (2021) Molecular dosimetry of temozolomide: Quantification of critical lesions, correlation to cell death responses and threshold doses, Molecular Cancer Therapeutics, 20 (10), 1789-1799

Aasland D., Götzinger L., Hauck L., Berte N., Meyer J., Effenberger M., Schneider S., Reuber E.E., Roos W.P., Tomicic M.T., Kaina B., Christmann M. (2019) Temozolomide induces senescence and repression of DNA rrepair pathways in glioblastoma cells via activation of ATR-CHK1, p21, and NF-kB, Cancer Research, 79, 99-113

Knizhnik A.V., Roos W.P., Nikolova T., Quiros S., Tomaszowski K.H., Christmann M., Kaina B. (2013) Survival and death strategies in glioma cells: autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damage, PLoS ONE, 2013;8(1):e5566

Regulation of repair genes

More than 500 proteins (enzymes and regulatory proteins) are involved in DNA repair and the DNA damage response. Their function on the DNA and their interaction in complex biochemical networks needs a fine-tuned regulation. DNA repair is subject to regulation at the transcriptional and epigenetic level. We were able to show that the DNA repair genes DDB2, XPC, XPF and XPG are robustly upregulated (induced) after exposure to genotoxins such as UV-light and benzo(a)pyrene as well as anticancer drugs. The damage polymerase Pol H is also induced, which affects not only the survival of the cells, but also their mutation frequency. MGMT is likely involved in an adaptive response. The repair gene is also regulated by glucocorticoids.

Christmann M., Kaina B. (2019) Epigenetic regulation of DNA repair genes and implications for tumor therapy, Mutation Research, 780:15-28

Aasland D., Reich T.R., Tomicic M.T., Switzeny O.J., Kaina B., Christmann M. (2018) Repair gene O6-methylguanine-DNA methyltransferase is controlled by SP1 and up-regulated by glucocorticoids, but not by temozolomide and radiation, J. Neurochem., 144, 139-151

Christmann M., Boisseau C., Kitzinger R., Berac C., Allmann S., Sommer T., Aasland D., Kaina B., Tomicic M.T. (2016) Adaptive upregulation of DNA repair genes following benzo(a)pyrene diol epoxide protects against cell death at the expense of mutations, Nucleic Acids Research, 44, 10727-10743

Christmann M., Kaina B. (2013) Transcriptional regulation of human DNA repair genes following genotoxic stress: trigger mechanisms, inducible responses and genotoxic adaptation, Nucl. Acids Res., 41, 8403-8420

A hot topic: Thresholds in genotoxicity and cell death

If DNA repair protects against mutations and cancer, it is reasonable to assume that an adaptive upregulation of DNA repair produces a threshold of carcinogenic exposures below which no or few effects are evident. So far, it has been assumed that there are no threshold doses for radiation and chemical carcinogens, i.e. even the smallest doses are carcinogenic. This concept is currently on the test bench. What is certain is that the repair enzyme MGMT protects very efficiently against O⁶-methylguanine inducing alkylating agents, including N-nitrosamines from food (meat, sausage products) and tobacco. Dose-response curves on experimental systems, including mouse models, display a no-effect threshold if MGMT is expressed, and no threshold if MGMT is lacking. Induction of the genes DDB2 and XPC involved in nucleotide excision repair could also provide a threshold under adaptive conditions for mutagens inducing bulky lesions. In summary, our and other published data show that low-doses of O6-alkylating agents should be assessed differently than high-dose exposures.

Stratenwerth B., Geisen S.M., He Y., Beltzig L., Sturla S., Kaina B. (2021) Molecular dosimetry of temozolomide: Quantification of critical lesions, correlation to cell death responses and threshold doses, Molecular Cancer Therapeutics, 20 (10), 1789-1799

He Y., Kaina B. (2019) Are there thresholds in glioblastoma cell death responses triggered by temozolomide? Int J Mol Sci., 2019 Mar 28;20(7)

Fahrer J., Frisch J., Nagel G., Kraus A., Dörsam .,  Thomas A.D., Reißig S., Waisman A., Kaina B. (2015) DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis, Carcinogenesis, 36, 1235-1244

Thomas A.D., Fahrer J., Johnson G.E., Kaina B. (2015) Theoretical considerations for thresholds in chemical carcinogenesis (2015) Mutat. Res. Rev., 765, 56-67

Becker K., Thomas A.D., Kaina B. (2014) Does increase in DNA repair allow “tolerance-to-insult” in chemical carcinogenesis? Skin tumor experiments with MGMT overexpressing mice, Environ. Mol. Mutagenesis, 55, 145-150

Effect of Artesunate and Curcumin

Artemisinin and curcumin are natural substances that have long been widely used in Traditional Chinese Medicine (TCM). The artemisinin derivative artesunate is currently the first-line drug in the treatment of malaria. The mode of action is interesting: artesunate needs Fe, which is abundant in erythrocytes. As a result, it is activated by an internal peroxide group and forms ROS. This kills the plasmodium in the erythrocytes. We have shown that artesunate activation also happens in tumor cells, where ROS production is long-lasting, constantly producing oxidative DNA damage and DNA double-strand breaks until a threshold is reached at which the cell dies by apoptosis. The kinetics of DNA damage thus differs fundamentally from that after radiotherapy. Artesunate also inhibits DNA repair processes, which can increase the effect of anticancer drugs such as temozolomide.

Berte N., Lokan S., Eich M., Kim E, Kaina B. (2016) Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence, Oncotarget, 7, 67235-67250

Berdelle N., Nikolova T., Quiros S., Efferth T., Kaina B. (2011) Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks and the ATM/ATR damage response in cancer cells, Mol. Cancer Therap., 10, 2224-223

C.H. Li P., Lam E., Roos W.P., Zdienicka M.Z., Kaina B., Efferth T. (2008) Artesunate derived from traditional chinese medicine induces DNA damage and repair, Cancer Res., 68, 4347-4351

For the water-insoluble curcumin, which can be easily absorbed in oil-based curry dishes (through micelle formation), there is a large number of studies that indicate a health-promoting effect. We showed that mice that consumed micellar curcumin daily had a lower incidence of colon cancer than animals in the control group. These data support the notion that curcumin is effective in protecting against cancer. Curcumin in a very high dose range exerts toxic (apoptosis) and genotoxic effects. However, these concentrations cannot be reached when consumed as food and food supplement. The data are nevertheless interesting, since curcumin could kill tumor cells in cancer therapy. On this basis, curcumin is tested in supportive therapy.

Beltzig L., Frumkina A., Schwarzenbach C., Kaina B. (2021) Cytotoxic,genotoxic and senolytic potential of native and micellar curcumin, Nutrients, 13 (7):2385

Seiwert N., Fahrer J., Nagel G., Frank J., Behnam D., Kaina B. (2020) Curcumin administered as micellar solution suppresses intestinal inflammation and colon carcinogenesis, Nutrition and Cancer, 29:1-8

DNA repair in the immune system cells

Cells of the immune system make a significant contribution to protection against cancer because they can recognize and eliminate cancer cells at an early stage. Immunocompetent cells can be found in tumors, which have an influence on tumor growth and can determine the therapy. The modern methods of tumor immunotherapy are based on these fundamental findings. Since tumors are usually irradiated and/or treated with therapeutics that are genotoxic, the question arises as to the fate of immunocompetent cells in the tumor tissue. Dendritic cells (DCs) play a key role in the immune system. These are formed from monocytes that come from the bone marrow. We have shown that monocytes have a low ability to repair DNA and that this ability is regained when monocytes mature into macrophages and DCs. This is due in particular to the silencing and subsequent upregulation of the repair genes XRCC1, PARP1 and ligase III. The hypersensitivity of monocytes to chemical oxidants, radiation and alkylating agents may have an impact on tumor therapy (through depletion of DCs which are required for presenting tumor antigens to T cells). We have also suggested that monocyte’s hypersensitivity to ROS is a regulatory mechanism to prevent excessive immune responses in inflammatory tissues.

Berte N., Eich M., Heylmann D., Koks C., Van Gool S.W., Kaina B. (2021) Impaired DNA repair in mouse monocytes compared to macrophages and precursors, DNA Repair, 98:103037

Ponath V., Kaina B. (2017) Death of monocytes through oxidative burst of macrophages and neutrophils: killing in trans, PLoS ONE, 12(1):e0170347, 1-20

Bauer M., Goldstein M., Heylmann D., Kaina B. (2012) Human monocytes undergo excessive apoptosis following temozolomide activating the ATM/ATR pathway while dendritic cells and macrophages are resistant, PLoS ONE, 7(6):e39956

Bauer M., Goldstein M., Christmann M., Becker H., Heylmann D., Kaina B. (2011) Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress, https://pubmed.ncbi.nlm.nih.gov/22160723/Proc. Natl. Acad. Sci. USA, 108, 21105-21110

Briegert M., Kaina B. (2007) Human monocytes, but not dendritic cells derived from them, are defective in base excision repair and hypersensitive to methylating agents, Cancer Res., 67, 26-31

A comparison of the different immunocompetent cells in the blood showed that not only monocytes, but also peripheral lymphocytes (B and T cells) are extremely sensitive to radiation compared to DCs and macrophages. This high radiation sensitivity primarily affects non-stimulated lymphocytes and is due to ATM-related signaling and the high readiness of the cells to go into apoptosis after DNA damage.

Heylmann D., Ponath V., Kindler T., Kaina B. (2021) Comparison of DNA repair and radiosensitivity of different blood cell populations, Scientific Reports, 11(1):2478

Heylmann D., Badura J., Becker H., Fahrer J., Kaina B. (2018) Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response, Cell Death Dis.;9(11):1053

Heylmann D., Rödel F., Kindler T., Kaina B. (2014) Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells, Biochem. Biophys. Acta Rev. Cancer, 1846, 121-129

Heylmann D., Bauer M., Becker B., van Gool S., Bacher N., Steinbrink K., Kaina B. (2013) Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response, PLoS One, 8(12):e83384

DNA repair and brain cancer therapy

Compounds that induce O⁶-methylguanine in DNA are known to be neurotropic carcinogens, meaning they cause brain tumors. On the other hand, these substances (temozolomide, dacarbazine, etc.) are used in the therapy of gliomas as well as in the therapy of other tumors. This objection can be resolved by the fact that O⁶-methylguanine induced in the DNA by these substances is both carcinogenic and cytotoxic. Thus, if it is not repaired by MGMT it can transform cells and also kill tumor cells. In glioblastomas, MGMT is not expressed in up to 40% of cases. This tumor group has a relatively good prognosis. MGMT activity is determined using a radioactive enzyme assay that we have established at the institute. It can also be done by determining the MGMT promoter methylation. This correlates with MGMT downregulation and is now used worldwide as a surrogate marker. We have also established this method at the institute and - in cooperation with departments of pathology (Prof. Sommer) and neurosurgery (Prof. Ringel) - have shown that low MGMT enzyme activity and promoter methylation correlate with response to therapy. We were able to determine a threshold of 30 fmol/mg protein for the MGMT activity. The toxic damage induced by methylating drugs, which is important in the therapeutic dose range, is the minor lesion O⁶-methylguanine. We have studied in detail the pathway from damage detection, mismatch repair conversion into DNA double-strand breaks to apoptosis execution in glioblastoma cells and identified a couple of drug resistance markers (MGMT, MMR, DDR, factors involved in DSB repair by HR, inhibitors of apoptosis). Our most recent work has been in the field of senescence. We were recently able to show that most tumor cells do not die through apoptosis, but go into a dormant (senescent) state after temozolomide treatment. Like apoptosis, this process is triggered by O⁶-methylguanine. We examined the molecular processes more closely and were able to show that certain substances selectively kill senescent glioblastoma cells. This group of compounds, the senolytics, may play a significant role in glioma therapy in the future.

Beltzig L., Christmann M., Kaina B. (2022) Abrogation of cellular senescence induced by temozolomide in glioblastoma cells: SEarch for senolytics, Cells, 11(16):2588

Kaina B., Beltzig L., Strik H. (2022) Temozolomide - Kust a radiosensitizer? Front Oncol., 12:912821

Beltzig L., Schwarzenbach C., Leukel P., Frauenknecht K.B.M., Sommer C., Tancredi A., Hegi M.E., Christmann M., Kaina B. (2022) Senescence is the main trait induced by temozolomide in glioblastoma cells, Cancers, 14(9), 2233

Beltzig L., Stratenwerth B., Kaina B. (2021) Accumulation of temozolomide-induced apoptosis, senescence and DNA damage by metronomic dose schedule: A proof-of-principle study with glioblastoma cells, Cancers (Basel), 13(24):6287

Haas B., Ciftcioglu J., Jermar S., Weickhardt S., Eckstein N., Kaina B. (2021) Methadone-mediated sensitization of glioblastoma cells is drug and cell line dependent,https://pubmed.ncbi.nlm.nih.gov/33315125/ J Cancer Res Clin Oncol., 147(3):779-792

Kaina B., Beltzig L., Piee-Staffa A., Haas B. (2020) Cytotoxic and senolytic effects of methadone in combination with temozolomide in glioblastoma cells, Int. J. Mol. Sci., 21(19): 7006

Kaina B. (2019) Temozolomide in glioblastoma therapy: Role of apoptosis, senescence and autophagy. Comment on Strobel et al., Temozolomide and other alkylating agents in glioblastoma therapy, Biomedicines, 7 (4), 69

Kaina B., Christmann M. (2019) DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas, DNA Repair, 78:128-141

He Y., Roos W.P., Wu Q., Hofmann T.G., Kaina B. (2019) The SIAH1-HIPK2-p53ser46 damage reponse pathway is inivolved in temozolomide-induced glioblastoma cell death, Mol Cancer Res., 17(5):1129-1141

Aasland D., Götzinger L., Hauck L., Berte N., Meyer J., Effenberger M., Schneider S., Reuber E.E., Roos W.P., Tomicic M.T., Kaina B., Christmann M. (2019) Temozolomide induces senescence and repression of DNA repair pathways in glioblastoma cells via activation of ATR-CHK1, p21, and NF-kB, https://pubmed.ncbi.nlm.nih.gov/30361254/Cancer Research, 79, 99-113

Roos W.P., Frohnapfel L., Quiros S., Ringel F., Kaina B. (2018) XRCC3 contributes to temozolomide resistance of glioblastoma cells by promoting DNA double-strand break repair, Cancer Letters, 424:119-126

Tomaszowski K.H., Hellmann N., Ponath V., Takatsu H., Shin H.W., Kaina B. (2017) Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases, Scientific Reports, 7(1):13925

Christmann M., Kaina B. (2016) MGMT - A critical DNA repair gene target for chemotherapy resistance, in 2nd edition, M.R. Kelley and M.L. Fishel (edts): DNA Repair in Cancer Therapy, Molecular Targets and Clinical Applications, pp. 55-82

Switzeny O., Christmann M., Renovanz M., Giese A., Sommer C., Kaina B. (2016) MGMT promoter methylation determined by HRM in comparison to MSP and pyrosequencing for predicting high-grade glioma response, Clinical Epigenetics, 8: 49 pp

Berte N., Piée-Staffa A., Piecha N., Wang M., Borgmann K., Kaina B., Nikolova T. (2016) Targeting homologous recombination by pharmacological inhibitors enhances the killing response of glioblastoma cells treated with alkylating drugs, Mol. Cancer Therap., 5(11), 2665-2678

Nikolova T., Roos W., Krämer O., Strik H., Kaina B. (2017) Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling, Biochim. Biophys. Acta, 1868, 29-39

Tomaszowski K.H., Schirrmacher R, Kaina B. (2015) Multidrug efflux pumps attenuate the effect of MGMT inhibitors,  Mol. Pharmaceutics, 12, 3924-3934

Roos W.P., Quiros S., Krumm A., Mertz S., Switzeny O., Christmann M., Loquai C., Kaina B. (2014) B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells, Oncotarget, 5, 12607-12620

Eich M., Roos W.P., Nikolova T., Kaina B. (2013) Contribution of ATM and ATR to the resistance of glioblastoma and malignant melanoma cells to the methylating anticancer drug temozolomide, Mol. Cancer Therap., 12, 2529-2540

Christmann M., Verbeek B., Roos W.P., Kaina  B. (2011) O⁶-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry, Biochem. Biophys. Acta, Rev. Cancer, 1816, 179-190

Kaina B., Margison G., Christmann M. (2010) Targeting O⁶-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy, Cell. Mol. Life Sci. 67, 3663-3681

Wiewrodt D., Nagel G., Dreimüller N., Hundsberger T., Perneczky A., Kaina B. (2008) MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome, Int. J. Cancer, 122, 1391-1399

Koch D., Hundsberger T., Boor S., Kaina B. (2007) Local intracerebral administration of O⁶-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma, J. Neurooncology, 82, 85-89

Roos W.P., Batista L.F.Z., Naumann S., Wick W., Weller M., Menck C.F.M., Kaina B. (2007) Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O⁶-methylguanine, Oncogene, 26, 186-197

Batista L.F.Z., Roos W.P., Christmann M., Menck C.F.M., Kaina B. (2007) Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2 and DNA double-strand breaks, Cancer Res., 67, 11886-11895

Many of these projects were funded by the German Research Foundation and the Mildred Scheel Foundation (Deutsche Krebshilfe), as well as by donations and intra-university research funding. I would like to express my sincere thanks to the master's students and all the PhD and MD students involved, as well as to the cooperation partners.