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- Harmine and Piperlongumine revert TRIB2-mediated drug resistancePublication . Machado, Susana; Silva, Andreia; De Sousa-Coelho, Ana Luísa; Duarte, Isabel; Grenho, Inês; Santos, Bruno F; Mayoral-Varo, Victor; Megias, Diego; Sánchez-Cabo, Fátima; Dopazo, Ana; Ferreira, Bibiana I.; Link, WolfgangTherapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.
- Vanadium and Melanoma: A systematic reviewPublication . Amante, Cristina; De Sousa-Coelho, Ana Luísa; Aureliano, M.The application of metals in biological systems has been a rapidly growing branch of science. Vanadium has been investigated and reported as an anticancer agent. Melanoma is the most aggressive type of skin cancer, the incidence of which has been increasing annually worldwide. It is of paramount importance to identify novel pharmacological agents for melanoma treatment. Herein, a systematic review of publications including “Melanoma and Vanadium” was performed. Nine vanadium articles in several melanoma cells lines such as human A375, human CN-mel and murine B16F10, as well as in vivo studies, are described. Vanadium-based compounds with anticancer activity against melanoma include: (1) oxidovanadium(IV); (2) XMenes; (3) vanadium pentoxide, (4) oxidovanadium(IV) pyridinonate compounds; (5) vanadate; (6) polysaccharides vanadium(IV/V) complexes; (7) mixed-metal binuclear ruthenium(II)–vanadium(IV) complexes; (8) pyridoxal-based oxidovanadium(IV) complexes and (9) functionalized nanoparticles of yttrium vanadate doped with europium. Vanadium compounds and/or vanadium materials show potential anticancer activities that may be used as a useful approach to treat melanoma.