Abstract
Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCμ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective.
Highlights
Metastasis is a highly complex process and the principle cause of cancer-associated death
RX1 possessed moderate inhibition of platelet aggregation stimulated by PDPN or collagen, and strong inhibition on thrombin, ADP- or U46619-stimulated platelet aggregation. 2CP inhibited PDPN-induced platelet aggregation with the IC50 equivalent of 12.1 ± 4.8 μM (Figure 1B and Table 1), but had little effect on platelet aggregation induced by the C-type lectin-like receptor 2 (CLEC-2) agonist rhodocytin or either by thrombin, collagen, ADP or U46619 (Figure 1B and 1C)
The IC50s of 2CP for these agonists were all >100 μM (Table 1). These results indicate that 2CP selectively inhibits PDPNinduced platelet aggregation
Summary
Metastasis is a highly complex process and the principle cause of cancer-associated death. Less than 0.1% of cancer cells dislodged from the primary tumor site survives in the blood stream and causes metastasis [1]. A number of antiTCIPA agents for blocking cancer metastases have been developed [3,4,5,6]. Apyrase, tissue inhibitor of www.impactjournals.com/oncotarget metalloproteinase-4, BM-567, XV454 and Abciximab are among the agents that inhibit tumor cell-platelet interactions and cancer metastases [7,8,9,10,11]. Treatment of cancer patients with these agents usually causes an increase in bleeding risk because most of the anti-TCIPA agents act on the platelet haemostatic proteins [4, 5, 12, 13]. Development of anti-TCIPA agents that do not interfere with physiological haemostasis is crucial for their utility as part of an anti-cancer therapeutic regimen
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