Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

Abstract

Abstract. Radiotherapy and adjuvant chemotherapy have become the standard treatments for multiple types of cancer. Although cancer cells are usually sensitive to radiotherapy, metastasis and local failure still occur mainly due to developed resistance to radiotherapy. Thus, it is critical to improve therapeutics for cancer treatment. The present study demonstrated that third-generation bisphosphonate zoledronic acid (ZOL), even at a low concentration, augments the radiosensitivity of cancer cells exposed to ionizing radiation (IR) by inducing S-phase arrest and subsequently promoting apoptosis. This function of ZOL was associated with elevated levels of cyclin A and cyclin B in the S and M phases, as well as decreased p21 CIP1 expression. In addition, ZOL also inhibited malignant the invasiveness of cancer cells. Notably, these effects could be enhanced concurrently with IR. The present data indicated that combined treatment with ZOL plus IR may be a novel technique to augment the radiosensitivity of cancer cells. IntroductionRadiotherapy and adjuvant chemotherapy have become the standard treatments for multiple types of cancer, including esophageal and nasopharyngeal carcinoma (1,2). Although radiotherapy is widely used to treat early-stage tumors, patients with advanced-stage tumors often experience failure of treatment mainly due to resistance to radiotherapy, resulting in recurrence and distant metastases (2-6). Therefore, the development of potent and reliable radiosensitizers is necessary for improving overall treatment outcomes in cancer therapy.Zoledronic acid (ZOL) is a compound containing nitrogen and bisphosphonates, which harbors anti-reabsorption effects (7). ZOL is used as therapy for bone metastasis in malignancy and a number of metabolic disorders, including bone pain, bone fractures and hypercalcaemia (8,9). ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the isoprenoid biosynthetic pathway, and prevents prenylation of small guanosine triphosphate-binding proteins, including Rho, p21 ras , cell division cycle 42, Rac and Rab, which are essential for different cellular functions such as signal transduction and cell adhesion (7-9). ZOL is considered to possess antitumor activity, particularly in combination with chemotherapeutic anticancer drugs (10-12). This effect of ZOL could be observed on cancer cells derived from a variety of tumors, including breast, prostate and pancreatic cancers, by inducing cell apoptosis and inhibiting cell invasion, adhesion and angiogenesis (10-13). Currently, numerous patients with bone metastases secondary to a broad range of solid tumors are benefiting from the antitumor effects of ZOL (14).Our previous study demonstrated the synergistic cytotoxic effects of ZOL and ionizing radiation (IR) on esophageal squamous cell carcinoma and endothelial cells (15). Accordingly, combined treatment with ZOL plus IR may be an encouraging method to treat cancer with less side effects and complications, compared with the use of these agents alone (15)(16)(17)(18)(19...

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

“…In addition, treatment with carbon-ion beam irradiation combined with ZOL increased the number of cells in the G2/M phase, compared to the case for treatment with carbon-ion beam irradiation and ZOL alone, suggesting that the combination treatment significantly attenuated cell cycle progression. These findings are partially consistent with previous reports stating that ZOL augments the X-ray or γ-ray radiosensitivity of fibrosarcoma and nasopharyngeal carcinoma cells [22][23][24][25][26], indicating that ZOL not only enhances low LET photon beam radiosensitivity, but also high LET carbon-ion beam radiosensitivity in OSA cells.…”

“…These data suggest that ZOL acts as an inhibitor of both the PI3K/Akt-and MAPK-signaling pathways, thereby enhancing the effects of carbon-ion beam irradiation on OSA cells. These results support the findings of recent studies that the combination treatment with ZOL increased cytotoxic effects via suppression of the Pi3K/Akt and MAPK signaling pathways [24,26,41,42].…”

“…However, although carbon ion beam radiotherapy treatment has yielded promising results, the prognosis of OSA still remains unsatisfactory; developing novel combinational therapeutic strategies to further improve overall survival is required.Bisphosphonates comprise the most important class of osteoclast-mediated bone resorption inhibitors and are used extensively for treating skeletal diseases such as postmenopausal osteoporosis and tumor-induced osteolysis [20,21]. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption that has demonstrated efficacy in treating bone metastases in cancer patients with breast, prostate, lung, and other solid tumors [22][23][24]. ZOL significantly enhances radiation-induced apoptosis and decreases cell viability, suggesting that it may exhibit radiosensitizing effects [25][26][27][28][29][30][31][32][33].…”

The Effect of Polydeoxyribonucleotide Extracted from Salmon Sperm on the Restoration of Bisphosphonate-Related Osteonecrosis of the Jaw

“…Vascular endothelial growth factor (VEGF) is an inducer of angiogenesis due to its highly specific mitogen for endothelial cells [17]. However, ZA, one of most widely used BPs, reduces the mRNA and protein expressions of VEGF and decreases serum levels of VEGF and other cytokines, such as interleukin-17, involved in angiogenesis [18]. In PDRN treatment for diabetes and burns, VEGF is produced by the actions on adenosis A2 receptors [19], which may contribute to increased angiogenesis.…”

SBRT ve Zoledronik Asid Kombinasyonu Kemik Metastaz Tedavisinde Aditif veya Sinerjistik Etki Mi Yapar?

“…They achieved control of the local disease in 94% of patients followed for an average of 19.2 months. As a result, the combination of Zoledronate and SBRT in the treatment of vertebral metastasis was well tolerated and reported that it reduced the rate of vertebral collapse, effectively reduced pain, and provided good local tumor control without late neurological side effects (10). Lu et al examined the combination of radiofrequency ablation, 125I-seed, zoledronic acid or radiotherapy in patients with spinal metastasis percutaneous vertebroplasty.…”