Metastases are the main cause of death in cancer patients. However, few metastasis-specific targets have been exploited therapeutically. Blood platelets are well known to contribute to the poor survival of patients with advance cancers. Unfortunately, platelets are mandatory for human life due to their paramount function in hemostasis. In order to define new anti-metastasis therapies exhibiting a high specificity for the pathological tumor cell-platelet interactions without abrogating normal platelet functions we developed a high throughput assay that showed that pharmacological blockade of cysteinyl leukotriene receptor 1 (CysLT1) with two already FDA-approved drugs in asthma (Zarfirlukast and Montelukast), dose-dependently inhibited the mitogenic action of human platelets on human MDA-B02/Luc breast cancer cells. Both drugs had no impact on cell proliferation in presence of serum suggesting a specific alteration of platelet function. This effect was specific to CysLT1 as the CysLT2 inhibitor HAMI3379 remained inefficient even at high doses. All human breast cancer cells including MDA-B02/Luc cells used in this study did not express CysLT1 whereas platelets do suggesting that platelet-CysLT1 was the one contributing to the protumoral action of platelets. As described previously cysteinyl leukotriene D4 (LTD4), the strongest agonist of CysLT1, has no direct effect on platelet aggregation but instead potentiates the action of platelet agonists. We next injected MDA-B02/Luc cells into the tail artery of nude mice that received a daily treatment with Zafirlukast (0.4mg/kg per os). After 7 days bone marrow cells were collected and placed in culture in presence of puromycine for 14 day. After staining with crystal violet clones of tumor cells that colonized bone (TCB) were quantified. In these conditions Zafirlulast significantly inhibited by 90% the number of TCB. In order to confirm this anti-metastasis effect we used a syngenic animal model of spontaneous metastasis dissemination of murine 4T1 breast cancer cells after orthotopic xenograph in the mammary gland of BALB/c immunocompetent mice. Animals were treated with Zafirlukast (0.4mg/kg/day, i.p.), the common chemotherapeutic agent Paclitaxel (30mg/kg/2 days, i.p), or both drugs combined starting at day 3 post-tumor cell injections until sacrifice at day 12. Lungs were collected, minced, treated with collagenase and placed in culture for 14 days in presence of 6-Thioguanine. After staining with crystal violet clones of tumor cells that colonized the lungs (TCL) were quantified. In these conditions, the number of TCL was reduced by 88% with Zafirlulast compared with 60% with Paclitaxel. The combined treatment of Zafirlukast + Paclitaxel remarkably inhibited by 100% the number of TCL. In contrast, Zafirlukast alone or in combination with Paclitaxel had no significant effect on primary tumor growth. In conclusion we described for the first time that blockade of platelet-CysLT1 receptor altered the protumoral action of platelets and prevented breast cancer cell metastasis to bone and lungs.
Citation Format: Lou Saier, Olivier Peyruchaud. Pharmacological blockade of platelet-CysLT1 receptor counteracts platelet protumoral action and prevents breast cancer cell metastasis to bone and lungs [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT011.