Synergistic Anti-Tumor Effects of Zoledronic Acid and Radiotherapy against Metastatic Hepatocellular Carcinoma

Abstract

A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct antitumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumorassociated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects.

The Role of Palliative Radiotherapy in the Treatment of Spinal Bone Metastases from Head and Neck Tumors—A Multicenter Analysis of a Rare Event

“…The differing re-ossification rates may partly be explained by individual radiation sensitivities of the respective tumor types. However, the exact mechanism for recalcification of bone lesions following RT is only incompletely understood, and further co-factors, such as synergistic effects of systemic treatments, tumor micromilieu, different scoring systems, and additional patient characteristics, may contribute to the observed different recalcification effects [37]. In our analysis, pathologic fractures of SBM prior to RT and a corset prescription were found to correspond to inferior stabilization rates; in addition, the administration of immunotherapy and cetuximab before starting RT was associated with higher numbers of SBM scored stable pre-RT than without these treatment approaches.…”

Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

“…Previously, combined treatment of metastatic HCC with RT and ZA was reported to result in its unexpected regression. 119 This synergistic effect in anti-liver cancer may be associated with the decreased infiltration of TAMs and the adjusted immunological milieu afforded by ZA. 119 , 120 More recently, RT plus ZA treatment has been implicated in decreasing bone pain and improving overall survival in patients with bone metastases from HCC.…”

Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

“…M-CSF promotes survival and proliferation of osteoclast precursors, and their differentiation into mature phagocytes, including osteoclasts [ 51 , 52 ]. ZA inhibits the activity, aggregation and migration of osteoclast precursor cells and macrophage [ 17 , 20 , 43 , 53 ] to prevent the differentiation of osteoclasts and induce apoptosis [ 54 ]. It is demonstrated that in the presence of M-CSF, ZA also inhibits RANKL-induced upregulation of RANK mRNA to suppress the differentiation of osteoclasts [ 41 ].…”

“…ZA has a direct effect on cancer cell through inhibiting proliferation and migration of cancer cells and induces apoptosis in vitro [ 73 ] and in vivo [ 74 ] in multiple cancer types, such as neuroblastoma [ 21 ], breast cancer cells [ 75 ], prostate cancer [ 20 , 76 , 77 ], epidermoid cancer cells [ 78 ], pancreatic cancer [ 79 ]. Previous studies have shown that the use of ZA may significantly enhance apoptosis by elevating ROS levels in prostate carcinoma and salivary adenoid cystic carcinoma cell models [ 80 , 81 ].…”

“…ZA is the most widely used BP for its potent anti-resorptive activity, in addition, it inhibits the differentiation and apoptosis of osteoclasts [ 17 – 19 ]. It also has anticancer effects [ 15 , 20 ], including suppressing metastasis of cancer [ 21 , 22 ], inhibiting the angiogenesis [ 23 ], and the synergistic effect with other anticancer drugs [ 17 , 20 , 24 ]. Here, we want to elaborate the mechanisms of ZA in inhibition of differentiation and apoptosis of osteoclasts, as well as its anticancer effects, which may provide a new strategy for the treatment of cancer, especially cancer with bone metastasis.…”