Chemo- and radiotherapy sensitizing strategies in lung cancer
I. Aim of the project: To analyse and characterize the effect of phenothiazines on DNA damage responses in lung cancer
On the molecular level, chemo- and radiotherapy cause multiple DNA damage. These include single and double strand breaks of the DNA and trigger the cellular stress response. The tumor cell survival depends on the ability to arrest in the cell cycle, repair DNA, and inhibit or activate cell death mechanisms, e.g. apoptosis, necrosis, and mitotic catastrophe. Thus, the tumor cells can overcome DNA damage by efficient DNA repair, which, in part, explains the resistance of certain tumour types.
Non-homologous end joining and homologous recombination are principal DNA double strand breaks repair mechanisms. DNA-dependent protein kinase (DNA-PK), member of the PI3K-like protein kinase family, is the key component of non-homologous end joining repair mechanism. Attempts have been made to inhibit DNA-PK for chemo- and radiotherapy sensitization of tumours. Previously, our group identified phenothiazines, a class of heterocyclic dopamine receptor antagonists used as anti-psychotic treatment, as capable of inhibiting DNA-PK in vitro. One phenothiazine, trifluoperazine, has been shown to increase cytotoxicity of different DNA damaging agents, like ionizing radiation and bleomycin, by inhibiting the repair of DNA double strand breaks and sensitize towards apoptotic signaling (Zong D. et al., 2011). We recently found that phenothiazines may, when used in combination with direct acting chemotherapeutics, cause hyperactivation of DNA-PK and ATM as part of a chemotherapy sensitizing mechanism. Further studies aim to understand the role of phenothiazines as chromatin modulating agents and as controllers of initiation and maintenance of DNA damage responses.
The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non small cell lung carcinoma cells to DNA double-strand break induced cell death.
Mol. Cancer Ther. 2007 Aug;6(8):2303-9
Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer.
Cell Death Dis 2014 Mar;5():e1111
Dali Zong, PhD, National Institutes of Health / National Cancer Institute (NIH/NCI), Bethesda, MD, USA
II. Aim of the project: To analyse and characterize the radiotherapy sensitizing capacity of Tumor Treating Fields in lung cancer with focus on DNA repair mechanisms
Tumor Treating Fields (TTFields) (www.novocure.com) are low intensity, intermediate frequency alternating electric fields, which are able to inhibit tumor growth both in vitro in various cancer cell lines and in vivo in tumor-bearing animals (Kirson ED. et al., 2004, 2007). The combination of TTFields with chemotherapy, e.g. with pemetrexed in non-small cell lung cancer in vitro and in animal models, have also shown additive effects on tumor growth inhibition. Recently, TTFields have been approved by the FDA for the treatment of glioblastoma multiforme in combination with temozolomide (www.novocure.com).
So far, the TTFields mechanism of action is based on anti-mitotic effects. Thus, in the beginning of mitosis, the electric field is uniform within the cell, causing tubulin subunits to align with the direction of the field and inhibiting their polymerization to form a normal microtubule spindle. In a non-uniform electric field during cytokinesis, charges and dipoles move towards the high field density at the mitotic furrow, disrupting mitosis and disintegrating the daughter cells. The aim of the project is to investigate the potential of TTFields for sensitizing lung cancer to radiotherapy.
Disruption of cancer cell replication by alternating electric fields.
Cancer Res. 2004 May;64(9):3288-95
Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.
Proc. Natl. Acad. Sci. U.S.A. 2007 Jun;104(24):10152-7