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Review
. 2013 Dec;9(4):491-540.
doi: 10.1007/s11302-013-9372-5.

Purinergic signalling and cancer

Geoffrey Burnstock, Francesco Di Virgilio
Review

Purinergic signalling and cancer

Geoffrey Burnstock et al. Purinergic Signal. 2013 Dec.

Abstract

Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.

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Figures

Fig. 1
Fig. 1
Schematic diagram illustrating the different mechanisms by which P2 receptor subtypes might alter cancer cell function. P2Y1 and P2Y2 receptors could affect the rate of cell proliferation through altering the intracellular levels of cAMP by modulating adenylyl cyclase (AC) or by increasing intracellular calcium levels through the phospholipase C (PLC) pathway. P2X5 and P2Y11 receptor activation might switch the cell cycle from proliferation into a state of differentiation. The P2X7 receptor activates the apoptotic caspase enzyme system. (Reproduced from [10] with permission.)
Fig. 2
Fig. 2
a Effect of ATP (1 ml of 25 mM i.p.) on the fractional growth of HRPC DU145 tumour cells in vivo after 60 days initial growth and b effect of ATP (1 ml of 25 mM i.p.) on the growth of implanted DU145 tumour cells in vivo after 60 days of initial growth; the lower mouse received ATP treatment vs. no treatment in the upper mouse. (Reproduced from [32] with permission.)
Fig. 3
Fig. 3
Effect of daily intraperitoneal ATP (1 ml of 25 mM i.p.) from day 0 on the growth of freshly implanted human bladder TCC HT-1376 tumour cells in vivo. (Reproduced from [33] with permission.)
Fig. 4
Fig. 4
a Dose–response curve of the effect of combining ATP with mitomycin C (MMC) vs. MMC alone on the viability of human bladder TCC HT1376 cells in vitro. b The effect of combining mitoxantrone and ATP on the viability of HRPC PC-3 cells in vitro. All points are the mean (S.E.M.) unless occluded by the symbol. ***P < 0.001. (a Reproduced from [33] and b from [182] with permission.)
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