Zoledronic Acid Enhanced the Antitumor Effect of Cisplatin on Orthotopic Osteosarcoma by ROS‐PI3K/AKT Signaling and Attenuated Osteolysis

Abstract

Osteoclasts can interact with osteosarcoma to promote the growth of osteosarcoma. Cisplatin is common in adjuvant chemotherapy of osteosarcoma. However, due to chemoresistance, the efficacy is profoundly limited. Previous studies have found that zoledronic acid (ZA) has osteoclast activation inhibition and antitumor effect. However, the combined effect of ZA and cisplatin on osteosarcoma remains unclear. In vitro, the effects of ZA and cisplatin alone or in combination on 143B cell activity, proliferation, apoptosis, and ROS-PI3K/AKT signaling were detected. At the same time, the effect of ZA and cisplatin on osteoclast formation, survival, and activity was detected by TRAP staining and bone plate absorption test. These were further verified in mice. The results showed that in vitro, compared with the single treatment and control, the combination of ZA and cisplatin could significantly inhibit the activity and proliferation of 143B cells and induced their apoptosis and further promoted the generation of ROS and inhibited the phosphorylation of PI3K and AKT. ROS scavenger and the agonist of the PI3K/AKT pathway could reverse these results. In addition, cisplatin in synergy with ZA could significantly inhibit osteoclast formation and survival to reduce bone plate absorption. In vivo, compared with the single group, the tumor volume and cell proliferation were significantly reduced, apoptosis and necrosis of tumor cells increased, and TRAP+ osteoclasts and osteolysis destruction decreased in the combined group. In conclusion, ZA enhanced the antitumor effect of cisplatin on osteosarcoma by ROS-PI3K/AKT signaling, reducing the chemoresistance and osteoclast activation to enhance chemotherapy and inhibit osteolysis. And this present study raised the possibility that combining ZA and cisplatin may represent a novel strategy against osteosarcoma.

Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation

“…Right now, almost all the mechanisms of ferroptosis are associated with reactive oxygen species (ROS) ( Li et al, 2020 ). Given the role of ZA in regulating ROS production ( Sehitoglu et al, 2015 ; Wang et al, 2018 ; Liu et al, 2021 ), here we investigated whether ZA suppresses the growth of osteoclast by accelerating ferroptosis. We found that the ferroptosis-related marker such as the levels of Fe 2+ , MDA content, ROS level was obviously increased in the osteoclasts treated with ZA, suggesting the ZA induced the ferroptosis of osteoclasts.…”

Osteoporosis in Childhood Cancer Survivors: Physiopathology, Prevention, Therapy and Future Perspectives

“…Among BPs, Zoledronate (ZOL), Pamidronate (PAM) and Neridronate (NRD) are the most-used anti-osteoporotic agents in children. ZOL is used in children affected by cancer who are disease free for a prolonged time and also in cases of bone metastases [ 149 ], as adjuvant chemotherapy to reduce skeletal events [ 150 ]. Recently, Liu et al observed in their study a reduction in osteolysis with combined use of Cisplatin and ZOL (CisZol) in OS patients, due to a strong inhibition of osteoclastic differentiation [ 150 ].…”

How zoledronic acid improves osteoporosis by acting on osteoclasts

“…Excessive amounts of FPP and GGPP lead to protein prenylation impairment, this is a potential pathological feature of osteoporosis (Zameer et al, 2018). ZA is known as the gold standard for the treatment of osteoporosis because of its recognized role in attenuating bone resorption and osteoclast apoptosis by inhibiting FPPS in the mevalonate pathway (Figure 2) (Tang et al, 2017;Zameer et al, 2018;Chandra and Rajawat, 2021;Chen et al, 2021;Munoz et al, 2021). Targeted inhibition of FPPS by ZA blocks the synthesis of FPP and the downstream product GGPP, which prevents the prenylation of Rab GTPases (e.g., members of the Ras superfamily) and their binding proteins (Kimachi et al, 2011;Zameer et al, 2018;Soysa and Alles, 2019).…”