Attenuation of Cytotoxic Natural Product DNA Intercalating Agents by Caffeine

Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama 35899, USA.
Scientia Pharmaceutica 09/2011; 79(4):729-47. DOI: 10.3797/scipharm.1107-19
Source: PubMed


Many anti-tumor drugs function by intercalating into DNA. The xanthine alkaloid caffeine can also intercalate into DNA as well as form π-π molecular complexes with other planar alkaloids and anti-tumor drugs. The presence of caffeine could interfere with the intercalating anti-tumor drug by forming π-π molecular complexes with the drug, thereby blocking the planar aromatic drugs from intercalating into the DNA and ultimately lowering the toxicity of the drug to the cancer cells. The cytotoxic activities of several known DNA intercalators (berberine, camptothecin, chelerythrine, doxorubicin, ellipticine, and sanguinarine) on MCF-7 breast cancer cells, both with and without caffeine present (200 μg/mL) were determined. Significant attenuation of the cytotoxicities by caffeine was found. Computational molecular modeling studies involving the intercalating anti-tumor drugs with caffeine were also carried out using density functional theory (DFT) and the recently developed M06 functional. Relatively strong π-π interaction energies between caffeine and the intercalators were found, suggesting an "interceptor" role of caffeine protecting the DNA from intercalation.

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Available from: William N Setzer, Aug 14, 2014
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    • "This mechanism of protection is known as " interceptor " mode of CAF and other methylxanthines action and was proposed by Bedner et al. [19]. The " interceptor " mode of CAF was described and analyzed for HCAs [15] and several other aromatic compounds: ethidium bromide [20] [21], propidium iodide [19] [20], quinacrine mustard, ICR170, ICR191 [22], proflavine [23], and several anticancer drugs [17] [24] [25]. Similar mechanism was also described for interaction of chlorophyllin (CHL) [26] and other natural constituents of human diet [27] with several aromatic compounds. "
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    • "At higher concentrations (>10 mM), caffeine potentiates the toxic effect [36]. To date, it is known that, on simultaneous addition or right after the main drug, CAF diminishes the toxicity of the antitumour antibiotics doxorubicin [30, 31, 33, 37–39], mitoxantrone [32] [33] [37] [39], ellipticine [33] [38], amsacrine [34], camptothecins [38] [40], and phenothiazine drugs [41] as well as the aromatic mutagen ethidium bromide [42] and aromatic neurotoxin tetrahydropyridine [43]. The " protector " effect has also been reported with respect to the aromatic mutagen quinacrine, ICR-191, ICR-170, IQ-type heterocyclic aromatic amines, and neocarzinostatin in the presence of caffeine and its derivatives [44] [45] [46] [47]. "
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