RESUMO
It is well reported in the literature that caffeine, the most consumed alkaloid around the world, enhances the anticancer effects of the drug cisplatin by inhibiting DNA repair by the cellular machinery. Here, we perform single-molecule force spectroscopy assays with optical tweezers to show that caffeine enhances the toxicity not only of cisplatin but also of various different platinum-based drugs already at the molecular level, using samples containing only double-stranded (ds)DNA, platinum drugs, and the alkaloid in a simple phosphate buffer, that is, completely out of the complex environment found inside real living cells. In fact, our results show that caffeine acts as an allosteric catalyst which increases the effective equilibrium binding constant between DNA and the platinum drugs, also interfering in the cooperativity of the binding reactions. To the best of our knowledge, this is the first time that such a property of caffeine was demonstrated and characterized from a pure physicochemical perspective, outside the cellular environment. Thus, the present work provides new insights into the use of this alkaloid for current chemotherapeutic applications.
Assuntos
Antineoplásicos , Cisplatino , Antineoplásicos/química , Cafeína/farmacologia , Cisplatino/farmacologia , DNA/química , Análise EspectralRESUMO
Melanoma accounts for only 4% of all skin cancers but is among the most lethal cutaneous neoplasms. Dacarbazine is the drug of choice for the treatment of melanoma in Brazil through the public health system mainly because of its low cost. However, it is an alkylating agent of low specificity and elicits a therapeutic response in only 20% of cases. Other drugs available for the treatment of melanoma are expensive, and tumor cells commonly develop resistance to these drugs. The fight against melanoma demands novel, more specific drugs that are effective in killing drug-resistant tumor cells. Dibenzoylmethane (1,3-diphenylpropane-1,3-dione) derivatives are promising antitumor agents. In this study, we investigated the cytotoxic effect of 1,3-diphenyl-2-benzyl-1,3-propanedione (DPBP) on B16F10 melanoma cells as well as its direct interaction with the DNA molecule using optical tweezers. DPBP showed promising results against tumor cells and had a selectivity index of 41.94. Also, we demonstrated the ability of DPBP to interact directly with the DNA molecule. The fact that DPBP can interact with DNA in vitro allows us to hypothesize that such an interaction may also occur in vivo and, therefore, that DPBP may be an alternative to treat patients with drug-resistant melanomas. These findings can guide the development of new and more effective drugs.