Despite extraordinary advances that have been achieved in the last few decades, cancer continues to represent a leading cause of mortality worldwide. Lethal cancer types ultimately become refractory to standard of care approaches; thus, novel effective treatment options are desperately needed. Tumor Treating Fields (TTFields) are an innovative non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity. TTFields are low intensity (1-3 V/cm), intermediate frequency (100-300 kHz) alternating electric fields delivered to cancer cells. In patients, TTFields are applied using FDA-approved transducer arrays, orthogonally positioned on the area surrounding the tumor region, with side effects mostly limited to the skin. The precise molecular mechanism of the anti-tumor effects of TTFields is not well-understood, but preclinical research on TTFields suggests it may act during two phases of mitosis: at metaphase, by disrupting the formation of the mitotic spindle, and at cytokinesis, by dielectrophoretic dislocation of intracellular organelles leading to cell death. This review describes the mechanism of action of TTFields and provides an overview of the most important in vitro studies that investigate the disruptive effects of TTFields in different cancer cells, focusing mainly on anti-mitotic roles. Lastly, we summarize completed and ongoing TTFields clinical trials on a variety of solid tumors.
Radiation therapy resistance remains a persistent clinical challenge in the treatment of multiple different cancer types. Better appreciation of novel molecular targets to improve radiation therapy efficacy is needed. TWIST1 is an epithelial-mesenchymal transcription factor whose expression is linked to therapy resistance, including radioresistance, in cancer. We have shown previously that the harmala alkaloid harmine degrades TWIST1 and possess anti-tumor activity. We hypothesized that harmine may radiosensitize cancer cells via downregulation of TWIST1. We examined the effects of harmine combined with radiation (RT) on two TWIST1 overexpressing tumor cell lines, A549 human non-small cell lung cancer (NSCLC) cells and the LMT mouse-derived hepatocellular cancer cell line (HCC), both with doxycycline-inducible Twist1 expression. We also used the LM mouse-derived HCC cell line without Twist1 expression as a control. In vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics, and protein expression in pathways important for cancer cell survival and radioresistance were performed. Harmine alone exhibited anti-cancer activity irrespective of Twist1 expression as shown by decreased clonogenic survival. Harmine caused a supra-additive radiosensitization in all cancer cell lines with radiation enhancement ratios between 1.05 – 3.04. In vivo we are evaluating tumor growth delay and effects of combined harmine and RT treatment in a NSCLC hind-flank tumor growth model. Mechanistic elucidation of these results, studies on normal cells, and in vivo validation are ongoing. Citation Format: Caleb R.P. Smack, Audrey Lafargue, Christine Lam, Francesca A. Carrieri, Ismaeel Siddiqui, Hailun Wang, Phuoc T. Tran. The harmala alkaloid harmine as a novel cancer cell radiosensitizer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-030.
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