Low pH increases the anti-proliferative capacity of NSAIDs
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1
University of Regensburg, Germany
Background and aim. We recently described novel COX-independent effects of the non-steroidal inflammatory drug (NSAID) diclofenac, which significantly diminished MYC expression and glucose metabolism in tumor cells in vitro and in vivo. It is well known that the accelerated glucose metabolism in tumor cells leads to lactic acid export and subsequently strong acidification of the tumor milieu. Therefore, we analyzed whether the effect of NSAIDs on tumor cell proliferation depends on the extracellular pH.
Methods. Different tumor cell lines (melanoma, prostate carcinoma, leukemia) were cultured with different concentrations of the non-selective COX-inhibitors diclofenac, diflunisal and ASA under different pH conditions. Cell proliferation was analyzed by thymidine incorporation and MYC expression was followed by Western Blot analysis.
Results. Clinically relevant concentrations of diflunisal inhibited tumor cell proliferation of various tumor cell lines comparable to diclofenac under normal physiological pH (pH 7.2). When we mimicked the tumor milieu by setting the pH to 6.9, the potency of both NSAIDs was increased, suggesting a pH-dependent transport into tumor cells. Further analysis showed that both substances decreased MYC expression, however only at high drug concentrations, indicating that MYC regulation is not responsible for the anti-proliferative effect of diflunisal. Next, we combined both substances under different pH conditions. Proliferation was further decreased especially under acidic conditions. In contrast, the anti-proliferative effect of the classical chemotherapeutic drug gemcitabine was not pH-dependent. However, NSAIDs supported the anti-proliferative effect of low gemcitabine concentrations.
Conclusions. In summary, our data show that the tumor pH has a strong impact on the inhibitory effects of NSAIDs on tumor cells. Diflunisal and diclofenac hold potential as clinically applicable drugs supporting established cancer therapies. This new aspect should be considered in tumor combination therapies.
Keywords:
tumormetabolism,
Diclofenac,
Diflunisal,
pH,
Cancer
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
6. pH control of immune functions and tumor cell plasticity
Citation:
Gottfried
E,
Lang
S,
Andreesen
R,
Herr
W and
Kreutz
M
(2014). Low pH increases the anti-proliferative capacity of NSAIDs.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00018
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Received:
19 Jan 2014;
Published Online:
07 Feb 2014.
*
Correspondence:
Dr. Eva Gottfried, University of Regensburg, Regensburg, Germany, Eva.Gottfried@ukr.de