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Nisin Augments Doxorubicin Permeabilization and Ameliorates Signaling Cascade during Skin Carcinogenesis

Simran Preet*, Satish K Pandey, Navjot Saini, Ashwani Koul and Praveen Rishi

Background: Multidrug resistance exhibited by cancerous cells has proved to be a big hurdle in the development of an effective anti-cancer therapy. We previously demonstrated nisin-doxorubicin adjunct therapy to exhibit strong additive anti-cancer effect against DMBA –induced murine skin carcinogenesis but the mechanism remained unexplored.

Methods: The in vivo tumoricidal activity of the combination was validated in terms of animal bioassay observations while ex vivo anti-cancer effect was monitored by employing HaCat cell lines.

Results: The combination was found to be additive in vivo as evidenced by larger decreases in mean tumor burden and tumor volumes. The IC50 values of nisin and DOX alone were evaluated to be 16 μg/ml and 4 μg/ml respectively while the sub-inhibitory concentration of DOX was reduced to 2 μg/ml when nisin was used as an adjunct. Q values calculated using MTT assays indicated the combination to be synergetic than additive. The mechanism was found to involve enhanced membrane permeabilization as well as reduced expression of NF-Κb, TNF-α, TNF-β, IL-1 and IL- 6.

Conclusion: As combined effect of nisin and DOX even at halved concentrations was significantly higher than either drug alone, these observations might help in lowering the chemotherapeutic doses of DOX thereby decreasing its associated side effects.