The search for novel anti-cancer drugs is a never ending story, since cancer is becoming a more and more important cause of death amongst humans. More than 80% of all anti-cancer drugs are directed towards the apoptosis pathway of tumour cells and are cytotoxic upon activating said pathway.
A large number of cancer cells such as glioblastomas (brain cancers), brain metastases, melanomas, pancreatic cancers, lung cancers of the NSCLC-type, refractory prostate cancers (HRPC), breast cancers such as triple negatives and other types are naturally resistant to apoptosis and cannot be treated by the many known drugs and chemotherapeutics. Development of new compounds having cytotoxic and/or cytostatic effects in tumour or cancer cells, and particularly in tumour or cancer cells which are resistant to apoptosis, is of considerable importance.
A naturally-occurring beta carboline, harmine, has been previously isolated from plants such as the Middle Eastern plant harmal or Syrian rue (Peganum harmala) and the South American vine (Banisteriopsis caapi) and shown to exhibit anti-cancer properties. However, previous reports demonstrated that harmine and its derivatives caused remarkable acute neurotoxicity characterized by tremble, twitch, and jumping in experimental mice model. Results of investigation on the in vitro anti-tumour activity of harmine and certain of its derivatives showed that these compounds had significant inhibition effect on several cultured tumour cell lines, such as HeLa cells (cervical carcinoma), S-180 cells (sarcoma), BEL-7402 cells (hepatoma), MGC-803 cells (gastric carcinoma), CNE2 cells (nasopharyngeal carcinoma), MA782/5S cells (breast cancer) and K562 cells (leucocythemia) (Wu, US 20090227619). EP 0357122 showed cytostatic properties of certain beta-carbolines.
Moreover, harmine and certain of its derivatives exhibited DNA intercalation capacity and topoisomerase I inhibition, which was related to their anti-tumour activity (Cao et al., 2005, Biochem. Biophys. Res. Com. 338: 1557-63).
Additionally, harmine was repeatedly shown to inhibit the protein kinase DYRK1A (Göckler, 2009, FEBS J. 276(21): 6324-37; Seifert, 2008, FEBS J. 275(24): 6268-80; Bain et al., 2007, Biochem J 408: 297-315). Over-expression of the DYRK1A kinase (dual specificity tyrosine-phosphorylated and regulated kinase 1a) has been implicated in multiple diseases or disorders or syndromes prominently including cancer, tumorigenesis and uncontrolled cell proliferation (Laguna et al., 2008, Dev Cell. 15(6): 841-53), but also Alzheimer disease, Pick disease (Ferrer et al., 2005, Neurobiol Dis. 20(2): 392-400) and Down Syndrome (Lepagnol-Bestel et al., 2009, Hum Mol Genet. 18(8): 1405-14).
Moreover, caspase-9 is a substrate of DYRK1A: inhibition of DYRK1A, by, e.g., harmine, induces the activation of caspase-9 and leads to massive apoptosis in different human cell types (Seifert et al., supra). It was also shown that melanomas are intrinsically resistant to pro-apoptosis stimuli and over-express DYRK1A (de Wit et al., 2002, Melanoma Res 12: 57-69). Recently, it was shown that harmine could reverse resistance to anticancer drugs by inhibiting BCRP (Ma et al., 2010, Phytother. Res. 24(1): 146-9).
There is therefore a continuous need in the art for identifying novel anti-proliferative drugs and for improving the efficacy of existing anti-proliferative treatments by combining the latter with novel anti-proliferative drugs.