Attenuation of cytotoxic natural product DNA intercalating agents by caffeine

Abstract

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.

Keywords: Caffeine; Cytotoxicity; DNA Intercalation; Density Functional Theory; π-π Complex.

Fig. 1

Modulation of DNA intercalation by caffeine via “interceptor” (left) or “protector” (right) interactions [15].

Fig. 2

Lowest-energy orientation of the π–π complex between berberine and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with berberine (tube model). (B) Molecular dipoles of berberine (top) and caffeine (bottom). (C) LUMO of berberine (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with berberine in the lowest-energy orientation. (E) Electrostatic potential maps of berberine (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between berberine and caffeine.

Fig. 3

Lowest-energy orientation of the π–π complex between camptothecin and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with camptothecin (tube model). (B) Molecular dipoles of camptothecin (top) and caffeine (bottom). (C) LUMO of camptothecin (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with camptothecin in the lowest-energy orientation. (E) Electrostatic potential maps of camptothecin (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between camptothecin and caffeine.

Fig. 4

Lowest-energy orientation of the π–π complex between chelerythrine and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with chelerythrine (tube model). (B) Molecular dipoles of chelerythrine (top) and caffeine (bottom). (C) LUMO of chelerythrine (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with chelerythrine in the lowest-energy orientation. (E) Electrostatic potential maps of chelerythrine (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between chelerythrine and caffeine.

Fig. 5

Lowest-energy orientation of the π–π complex between doxorubicin and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with doxorubicin (tube model). (B) Molecular dipoles of doxorubicin (top) and caffeine (bottom). (C) LUMO of doxorubicin (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with doxorubicin in the lowest-energy orientation. (E) Electrostatic potential maps of doxorubicin (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between doxorubicin and caffeine.

Fig. 6

Lowest-energy orientation of the π–π complex between ellipticine and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with ellipticine (tube model). (B) Molecular dipoles of ellipticine (top) and caffeine (bottom). (C) LUMO of ellipticine (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with ellipticine in the lowest-energy orientation. (E) Electrostatic potential maps of ellipticine (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between ellipticine and caffeine.

Fig. 7

Lowest-energy orientation of the π–π complex between sanguinarine and caffeine. (A) Face-to face orientation of caffeine (ball and spoke model) in its lowest-energy orientation with sanguinarine (tube model). (B) Molecular dipoles of sanguinarine (top) and caffeine (bottom). (C) LUMO of sanguinarine (top) and HOMO of caffeine (bottom). (D) Frontier molecular orbital overlap of caffeine with sanguinarine in the lowest-energy orientation. (E) Electrostatic potential maps of sanguinarine (top) and caffeine (bottom). (F) Electrostatic potential map of the lowest-energy π–π complex between sanguinarine and caffeine.