Abstract
BackgroundBromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years. As such, the potential values of these agents in cancer therapy have been variably reported in the literature. In the present study, the efficacy of bromelain and N-acetylcysteine in single agent and combination treatment of human gastrointestinal carcinoma cells was evaluated in vitro and the underlying mechanisms of effect were explored.MethodsThe growth-inhibitory effects of bromelain and N-acetylcysteine, on their own and in combination, on a panel of human gastrointestinal carcinoma cell lines, including MKN45, KATO-III, HT29-5F12, HT29-5M21 and LS174T, were assessed by sulforhodamine B assay. Moreover, the influence of the treatment on the expression of a range of proteins involved in the regulation of cell cycle and survival was investigated by Western blot. The presence of apoptosis was also examined by TUNEL assay.ResultsBromelain and N-acetylcysteine significantly inhibited cell proliferation, more potently in combination therapy. Drug-drug interaction in combination therapy was found to be predominantly synergistic or additive. Mechanistically, apoptotic bodies were detected in treated cells by TUNEL assay. Furthermore, Western blot analysis revealed diminution of cyclins A, B and D, the emergence of immunoreactive subunits of caspase-3, caspase-7, caspase-8 and cleaved PARP, withering or cleavage of procaspase-9, overexpression of cytochrome c, reduced expression of anti-apoptotic Bcl-2 and pro-survival phospho-Akt, the emergence of the autophagosomal marker LC3-II and deregulation of other autophagy-related proteins, including Atg3, Atg5, Atg7, Atg12 and Beclin 1. These results were more prominent in combination therapy.ConclusionWe report for the first time to our knowledge the growth-inhibitory and cytotoxic effects of bromelain and N-acetylcysteine, in particular in combination, on a panel of gastrointestinal cancer cell lines with different phenotypes and characteristics. These effects apparently resulted from cell cycle arrest, apoptosis and autophagy. Towards the development of novel strategies for the enhancement of microscopic cytoreduction, our results lay the basis for further evaluation of this formulation in locoregional approaches to peritoneal surface malignancies and carcinomatosis.
Highlights
Bromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years
In KATO-III cells, synergistic effects were evident in all treatment groups, except for two groups with the lowest concentration of NAC whereby consistent strengthening of the synergy accompanied higher concentrations of bromelain/NAC
Apart from the antagonistic effects observed in two groups with the lowest concentration of NAC (NAC 1 mM combined with bromelain 5 and 10 μg/mL), bromelain-NAC interaction in HT29-5F12 cells was revealed to be synergistic, with a slight strengthening at higher concentrations
Summary
Bromelain and N-acetylcysteine are two natural, sulfhydryl-containing compounds with good safety profiles which have been investigated for their benefits and application in health and disease for more than fifty years. Novel modalities are needed to complement the current standard of care through enhancement of microscopic cytoreduction To this end, our research team at St George Hospital (Sydney, Australia), with an established Peritoneal Surface Malignancy Program since 1996 [7,8], has sought to develop novel locoregional approaches to peritoneal malignancies. A variety of agents have been tested for their potential value in such a strategy, among which bromelain and Nacetylcysteine (NAC) as two natural agents with good safety profiles have shown promise in our investigations. We report for the first time to our knowledge that bromelain and NAC, on their own and more potently in combination, inhibit growth and proliferation of gastrointestinal cancer cells and promote cell death in vitro
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