Anticancer properties of chitosan on human melanoma are cell line dependent

Abstract

Purpose: Chitosan, a natural macromolecule, is widely used in medical and pharmaceutical fields because of its distinctive properties such as bactericide, fungicide and above all its antitumor effects. Although its antitumor activity against different types of cancer had been previously described, its mechanism of action was not fully understood. Materials and Methods: Coating of chitosan has been used in cell cultures with A375, SKMEL28 and RPMI7951 cell lines. Adherence, proliferation and apoptosis were investigated. Results: Our results revealed that whereas chitosan decreased adhesion of primary melanoma A375 cell line and decreased proliferation of primary melanoma SKMEL28 cell line, it had potent pro-apoptotic effects against RPMI7951, a metastatic melanoma cell line. In these latter cells, inhibition of specific caspases confirmed that apoptosis was effected through the mitochondrial pathway and Western blot analyses showed that chitosan induced an up regulation of pro-apoptotic molecules such as Bax and a down regulation of anti-apoptotic proteins like Bcl-2 and Bcl-XL. More interestingly, chitosan exposure induced an exposition of a greater number of CD95 receptor at RPMI7951 surface, making them more susceptible to FasL-induced apoptosis. Conclusion: Our results indicate that chitosan could be a promising agent for further evaluations in antitumor treatments targeting melanoma. Point 1: This point is very interesting, notably to verify if lower doses could also affect melanoma cells and especially the RPMI7951 metastatic cancer cells. It could also be pertinent to minimize adverse effect on healthy cells. We have evaluated the effect of chitosan concentration on RPMI7951 cell line and normal primary human dermal fibroblasts and it is reported on Fig.5C (for caspase-3 activity) and D (for cell count using WST-1 test).Point 2: Previous the first submission, we had done tests to verify whether apoptosis induction was detectable on fibroblasts but not extensively. Thus, the remark of the reviewer was a chance to improve this paper. Chitosan effect was assessed on adhesion, proliferation and apoptosis of normal primary human dermal fibroblasts. As depicted in fig.5A, apoptotic morphology was not seen when fibroblasts were cultured on chitosan coating as well as no/low caspase activation (Fig.5C, even at high doses of Chitosan, and Fig.5F, even when cultures were continued for 6 days). However, it could be noted that the cell number was reduced ( Fig.5D and E), probably as a result of a reduced proliferation. In vivo, because fibroblasts, unlike cancer cells, have a very slow proliferation rate, chitosan should have a low action on these cells. Cell attachment was tested (Fig.5B) and, even if a delay could be observed in the presence of chitosan after 6 hours, virtually all fibroblasts had adhered on the plate. Point 3: Long term cultures (here 6 days) have been tested. Caspase activation increased substantially when RPMI7951 were seeded onto chitosan coated plates but such a phenomenon could not b...

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