A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo

Abstract

Minodronic acid (YM529) is a third-generation bisphosphonate (BP) that has been shown to directly and indirectly prevent proliferation, induce apoptosis, and inhibit metastasis of various types of cancer cells. In this study, we have investigated the therapeutic efficacy of YM529 against bladder cancer, both in vitro and in vivo. YM529 inhibited geranylgeranylation as well as farnesylation and reduced the growth of all seven bladder cancer cell lines in a dose-and time-dependent manner in vitro. YM529 demonstrated a good synergistic or additive antiproliferative effect when administered in combination with cisplatin or paclitaxel. Immunohistochemical study revealed YM529 inhibited the prenylation of Rap1A in vivo. YM529 administered systemically did not markedly inhibit the growth of visceral metastases but it showed a significant anticancer effect on bone metastases monitored by an in vivo imaging system. Moreover, intravesical YM529 demonstrated significant growth inhibition in a bladder cancer orthotopic model. No adverse effects were associated with the systemic as well as the intravesical treatment regimens. In conclusion, our study suggests that YM529 may be a potent anticancer agent for bladder cancer. The efficacy and safety of this BP as an agent for combination chemotherapies against bladder cancer should be verified by early-phase clinical trials.

Cancer cell killing via ROS: To increase or decrease, that is the question

“…4,44 The efficacy of minodronate on treatment especially of bone metastases from breast cancer has been proved through mice model and through clinical trials. 45,46 The immuno-enhancing properties of histamine in synergizing with IL-2 and IFNα to induce killing of human tumor cells also rely on its inhibitory effect on the NADPH oxidase in monocyte/ macrophages via H2-type histamine receptors. Through this mechanism, histamine protects NK cells and T cells against ROS-induced dysfunction and apoptosis and also maintains their activation by IL-2 and other cytokines used in cancer immunotherapy.…”

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

“…However, neither CTX nor ZOL had a significant effect on cell growth in SW1417 and RKO cells; these cells contain mutant BRAF (V600E) despite their wild‐type KRAS status, suggesting that both EGFR and BRAF might be critical determinants of ZOL‐CTX combination efficacy. According to previous reports, ZOL exerted antitumor effects by inhibiting prenylation of RAS in bladder cancer and myeloma cells 25, 34. However, to our knowledge, no previous reports have described an antitumor effect of ZOL in CRC, suggesting that ZOL may work in a tissue‐ or tumor‐specific manner.…”

“…In our current study, we therefore demonstrated the antitumor effect of ZOL using a clinically relevant concentration (0.1–10 μM) in combination with CTX. Furthermore, ZOL synergizes with chemotherapeutic agents such as docetaxel, paclitaxel, and cisplatin 34, 42. These findings suggest that ZOL might play an important role as an effector for cancer therapy.…”

Denosumab: a new option in the treatment of bone metastases from urological cancers

“…The first study showed that minodronic acid (also known as YM529), another third-generation bisphosphonate, had anticancer activity and synergistically augmented interferon-induced growth inhibition in vitro and in vivo 59. The second and third studies established luciferase-labeled human RCC and urothelial cancer cell models to investigate the inhibition of osteoclasts and of bone metastasis by minodronic acid in vivo 60. Minodronic acid administered systemically successfully showed significant anticancer efficacy in luciferase-labeled urothelial cancer cell bone metastases monitored using an in vivo imaging system 60.…”