Punzo Francesca, Tortora Chiara, Argenziano Maura, Pinto Daniela Di, Pota Elvira, Martino Martina Di, Paola Alessandra Di, Rossi Francesca
Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
Oncotarget. 2020 Jul 14;11(28):2763-2773. doi: 10.18632/oncotarget.27669.
Osteosarcoma is an aggressive bone tumor of the pediatric age. It is therefore important to improve conventional therapies (chemotherapy and surgery). Anticancer drugs often cause osteoporosis due to a misbalance of RANK/RANK-L/OPG pathway. Denosumab is a monoclonal antibody with high affinity and specificity to RANK-L, the ligand released by osteoblasts that enhances osteoclasts differentiation and bone resorption. It is used in osteoporosis and in other conditions characterized by bone mass loss. Doxorubicin is a chemotherapic drug used in several kinds of tumors, and also patients treated with it often develop osteoporosis. We investigated the effects of Denosumab alone and in combination with Doxorubicin, in two human osteosarcoma cell lines (MG63 and U-2 OS). We evaluated the effect of these treatments on apoptosis, cell cycle progression, invasion capacity and bone metabolism. We observed for the first time an anti-invasive effect of Denosumab in OS cells and confirmed its anti-osteoporotic activity also in Osteosarcoma. On the other hand, we demonstrate that Denosumab not only does not affect apoptosis and cell cycle progression, but when used in combination with Doxorubicin, it causes an unexpected reduction of its activity. These results indicate that the presence of Denosumab might inhibit the efficacy of the chemotherapic drug. In conclusion, while our results certainly support and confirm the efficacy of Denosumab in Osteoporosis, we discourage the use of Denosumab in addition to conventional chemotherapy in Osteosarcoma, even though, certainly further investigations are necessary to better clarify the clinical role of this monoclonal antibody in cancer.
骨肉瘤是一种发生于儿童期的侵袭性骨肿瘤。因此，改进传统疗法（化疗和手术）很重要。抗癌药物常常由于RANK/RANK-L/OPG信号通路失衡而导致骨质疏松。地诺单抗是一种对RANK-L具有高亲和力和特异性的单克隆抗体，RANK-L是由成骨细胞释放的配体，可增强破骨细胞分化和骨吸收。它用于治疗骨质疏松症及其他以骨量丢失为特征的病症。阿霉素是一种用于多种肿瘤治疗的化疗药物，接受该药物治疗的患者也常发生骨质疏松。我们研究了地诺单抗单独使用以及与阿霉素联合使用对两种人骨肉瘤细胞系（MG63和U-2 OS）的影响。我们评估了这些治疗对细胞凋亡、细胞周期进程、侵袭能力和骨代谢的作用。我们首次观察到地诺单抗在骨肉瘤细胞中具有抗侵袭作用，并证实了其在骨肉瘤中也具有抗骨质疏松活性。另一方面，我们证明地诺单抗不仅不影响细胞凋亡和细胞周期进程，而且当与阿霉素联合使用时，会意外降低其活性。这些结果表明地诺单抗的存在可能会抑制化疗药物的疗效。总之，虽然我们的结果肯定支持并证实了地诺单抗在骨质疏松症中的疗效，但我们不鼓励在骨肉瘤的常规化疗基础上加用地诺单抗，尽管当然还需要进一步研究以更好地阐明这种单克隆抗体在癌症中的临床作用。
