Potentiation of Lipid Peroxidation in B16F10 and B16F1 Melanoma Cells by Caffeine, a Methylxanthine Derivative: Relationship to Intracellular Glutathione

Abstract

Background: Caffeine has shown an inhibitory role in invasion and proliferation in melanoma pulmonary metastasis as well as in high-grade tissue sarcoma. However, little is known about its mechanism and possible role in metastatic cell lines. Materials and Methods: B16F10 and B16F1 cell lines of high and low metastatic potential were treated with caffeine at different time intervals with different doses. Reduced glutathione, glutathione S-transferase and lipid peroxides were estimated to evaluate the effect of caffeine. Results: Caffeine treatment showed glutathione depletion and increased lipid peroxidation with higher glutathione S-transferase activity in both B16F10 and B16F1 cell lines. However the effect of caffeine was dependent on the time factor as well as on the dose. Conclusions: Caffeine was an effective inhibitor of metastatic activity. Glutathione depletion in conjunction with increased lipid peroxidation was a potent indicator in the regulation of metastatic behavior of B16F10 and B16F1 melanoma cell lines.

Neocarzinostatin as a probe for DNA protection activity—molecular interaction with caffeine

“…Even though the physiological concentration of GSH can be high as 10 mM [66], whether the interaction between caffeine and GSH played a role in the caffeine‐involved inhibition mechanism is an interesting question. Caffeine is known to reduce cellular GSH level [67, 68], but seems with a relatively low efficiency compared to the DNA damage reactions induced by NCS. The GSH‐activated NCS–DNA reaction in general completes within 30 min [69], whereas cells treated with caffeine show no changes in GSH level up to 2 h [67].…”

“…Caffeine is known to reduce cellular GSH level [67, 68], but seems with a relatively low efficiency compared to the DNA damage reactions induced by NCS. The GSH‐activated NCS–DNA reaction in general completes within 30 min [69], whereas cells treated with caffeine show no changes in GSH level up to 2 h [67]. Furthermore, the decreased GSH level caused by caffeine might not be large enough to significantly inhibit NCS activity.…”

“…Furthermore, the decreased GSH level caused by caffeine might not be large enough to significantly inhibit NCS activity. A dose of 5 mM of caffeine in cells produces only up to 34% GSH reduction after a 3‐h incubation [67], and 100 mg/kg in rates results in merely 22.5% reduction after 4‐h treatment [68]. Although depletion of GSH results in a decrease in NCS‐mediated cytotoxicity and DNA damage [69–71], only 67% decrease in NCS activity is observed when cellular GSH is reduced by more than 99.9% [69].…”

Pharmacological potential of methylxanthines: Retrospective analysis and future expectations

“…That would be the case of skin (Huang et al 1997;Lu et al 2002;Lu et al 2006a), lung (Chung et al 1998;Lu et al 2006b) and mammary (Yang et al 2005) cancers. In mice (a 100 mg/kg dose) (Gude, Menon, and Rao 2001) and posteriorly in melanoma cell lines, (up to 5.0 mM and 3 h treatment) (Shukla and Gude 2003), caffeine was shown display anti-metastatic activity. Therefore, it was suggested that it inhibits the invasion and proliferation in melanoma pulmonary metastasis as well as in high-grade tissue sarcoma (Shukla and Gude 2003).…”

“…In mice (a 100 mg/kg dose) (Gude, Menon, and Rao 2001) and posteriorly in melanoma cell lines, (up to 5.0 mM and 3 h treatment) (Shukla and Gude 2003), caffeine was shown display anti-metastatic activity. Therefore, it was suggested that it inhibits the invasion and proliferation in melanoma pulmonary metastasis as well as in high-grade tissue sarcoma (Shukla and Gude 2003). It has also been suggested that, mechanistically, caffeine beneficial effects are p53 independent (Lu et al 2002) and may involve the promotion of cell cycle arrest in the G0/G1 phase in cancer cells, probably through suppression of cyclin D1-cdk4 complex activation and consequent inhibition of retinoblastoma protein phosphorylation (Hashimoto et al 2004).…”