Acetaminophen and DMSO modulate growth and gemcitabine cytotoxicity in FM3A breast cancer cells in vitro

Addition of antioxidants to chemotherapy is an unresolved problem in oncology. It is still an issue of debate, whether antioxidants may reduce rough cellular toxicity and thereby the systemic side effects of the chemotherapy, without sacrificing the anti-tumor efficacy. Gemcitabine is a rather new anti-cancer agent, which is quite potent against a range of drug resistant tumors, particularly breast cancer. Tumor-sensitivity towards gemcitabine can be increased with COX inhibitory anti-inflammatory agents and ribonucleotide reductase (RR) inhibitor flavopiridol. Acetaminophen and DMSO are two unique anti-inflammatory and anti-oxidant agents with unrelated structures, yet both capable to block RR and COX, simultaneously. Using plating efficacy and H-3-thymidine labeling, we monitored efficacy of acetaminophen and DMSO to modulate growth and gemcitabine sensitivity in FM3A breast tumor cells, which is highly used to study thymineless death induced by nucleotide-metabolism hemming drugs. Peculiarly, acetaminophen alone stimulated S-phase, which was not accompanied with enhanced plating, rather resulting in 40.3% growth inhibition at the 96 hour. DMSO alone significantly diminished both the plating and S-phase, which resulted in 71.7% growth inhibition at the 96 hour. Gemcitabine drastically reduced S-phase and plating until 72 hours, yet at 96 hours it lost its efficacy to suppress the S-phase with concomitant 2-fold rise in cell numbers in comparison to 72 hour time point. Both DMSO and acetaminophen brought S-phase to around zero percent in combination with gemcitabine until 48 hours, yet they both reduced early cytotoxicity of gemcitabine at the same time interval. However, at the 96 hour, they both strongly augmented gemcitabine efficacy to block S-phase and prevented the rise in plating. Acetaminophen and DMSO should be tested in animal models, whether they could augment efficacy and reduce the toxicity of gemcitabine.