F4Potential therapeutic combination of beta-blockers and trabectedin in metastatic soft tissue sarcoma and ovarian cancer

Trabectidin has been approved as single agent for second-line therapy of soft tissue sarcomas (STS) such as liposarcoma (LS) and leiomyosarcoma (LMS) and for the treatment of patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Clinical evidence revealed that beta-adrenergic receptor antagonists such as propranolol, could increase the effectiveness of vinblastine in the treatment of sarcoma patients. In order to realize tailored therapy toward different histological subtypes of STS and of ovarian cancer, the investigation of ß-adrenergic receptors (ß-ARs) as appropriate targets in a combined treatment with Trabectedin was evaluated. After determining the expression of ß-ARs in ovarian and sarcoma cell lines, we started combining propranolol with Trabectedin. Our results demonstrated that propranolol strongly enhances the response to Trabectedin in both A2780 ovarian cancer cells resistant to carboplatin and in the sensitive cell lines OV2008. The evaluation of the synergism among drugs was assayed both in 2D and in 3D cells models. The analysis of cell cycle showed that Trabectedin blocked the cells in S-phase and the addition of propranolol farther caused the accumulation of cells in both G0/G1 and S-phase. Such effects resulted in a strong induction of apoptosis in the combination compared to single treatment. Notewhorty the efficacy of the combination was maintained in stress inducted condition (10µM norepinephrine-NE). In agreement with cytotoxic results, the combination still induced apoptosis even after NE stimulation. We also tested the therapeutic potential of combining propranolol to Trabectedin in the treatment of sarcoma cells. Both drugs alone were effective in reducing cell proliferation of LS cells stronger than LMS cells, and also the combination was more cytotoxic in LS cells than LMS cells. Interestingly, the activation with physiological concentration of β-ARs agonist Norepinephrine (NE) 100mM, did not resulted in reduced sensitivity to both propranolol and Trabectedin, while the stress induced concentration of NE 10μM resulted in reduced sensitivity to each single agent in LMS model. In conclusion blockage of β-adrenergic receptors enhances Trabectedin effectiveness, therefore further evaluation of underlying mechanisms of drugs synergism are warranted in order to provide a strong rational for suggesting this combination in the treatment of sarcoma and ovarian cancer patients.