Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Abstract

Abstract. Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

Reactive Oxygen Species and Autophagy Associated Apoptosis and Limitation of Clonogenic Survival Induced by Zoledronic Acid in Salivary Adenoid Cystic Carcinoma Cell Line SACC-83

“…Production of ROS is an underlying mechanism of chemotherapy and radiotherapy [44]. Previous studies have shown that combined application of ZOL with panobinostat or ionizing radiation significantly enhanced apoptosis by elevating ROS levels [45], [46]. Here, we found that ZOL alone can induce apoptotic cell death and inhibit colony formation accompanied by an increase of ROS.…”

Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways

“…19, 40 A direct effect of ZOL as a single agent on ROS generation has not been shown before; however, a recent report demonstrated that the increased intracellular ROS levels and the cytotoxic effect induced by ionizing radiation in cancer cells are enhanced by cotreatment with ZOL and that this effect is reduced by NAC. 41 Notably, isoprenoids such as GGPP and FPP, which are inhibited in the cells treated with ZOL, are involved in the positive modulation of several nonsteroid isoprenoids (e.g., heme-A, coenzyme-Q10, and dolichols) that are related to antioxidant status. 42 In light of these data, we can hypothesize that ZOL treatment may potentiate HDACi-induced oxidative stress by inhibiting the biosynthesis of antioxidant isoprenoids.…”

Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells

“…In addition to its bone-protective effects, ZA can prevent tumor progression (8). Due to its inhibition of the prenylation of small GTP-binding proteins, such as Ras, ZA inactivates Ras signaling and inhibits Ras-dependent cell proliferation (9)(10)(11).…”