The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate

Kuroda, Junya; Kimura, Shinya; Segawa, Hajime; Kobayashi, Yutaka; Yoshikawa, Toshikazu; Urasaki, Yoshimasa; Ueda, Takanori; Enjo, Fumio; Tokuda, Harukuni; Ottmann, Oliver G.; Maekawa, Taira

doi:10.1182/blood-2003-01-0305

Cited by 114 publications

(125 citation statements)

References 41 publications

(41 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…These findings suggested that the effects of ZOL in osteosarcoma cells were affected by P-gp. However, we have previously reported that the antitumour effects of ZOL against leukaemic cell lines are not affected by P-gp (Kuroda et al, 2003). This discrepancy could be explained by the differences on the activity of ZOL against leukaemic cells and osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 79%

“…Because MTX activity was changed by the sensitivity of cells and the pharmacokinetics of the drugs, MTX has major cytotoxic effects on cells in the S phase and accumulates in cells in the G 1 to early S phase and later into the G 2 /M phase (Lorico et al, 1990;Yamauchi et al, 2005). On the contrary, ZOL has major cytotoxic effects in the S phase and accumulates in cells in the late S and early G 2 phases (Kuroda et al, 2003). If cells were treated MTX followed by ZOL, the combined effect may be observed to augment each other.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid YM529 show direct antitumour effects and synergistically augments the effects of anticancer agents in various cancer cell lines (Kuroda et al, 2003;Kimura et al, 2004;Matsumoto et al, 2005;Segawa et al, 2005;Yuasa et al, 2005). Recently, several investigators have reported the antiosteosarcoma effects of third-generation BPs in vitro (Evdokiou et al, 2003;Kubista et al, 2006;Kubo et al, 2006;Tenta et al, 2006) and in vivo Ory et al, 2005).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

et al. 2007

View full text Add to dashboard Cite

Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to possess direct antitumour activity. We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects of ZOL which is clinically available. In addition to ZOL alone, we evaluated the concurrent or sequential combined effects of ZOL with other anticancer agents against murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or GEM against osteosarcoma cells. These findings suggest that combined administration of ZOL with other anticancer agents may improve the osteosarcoma treatment.

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Bisphosphonate (BP) is an inhibitor of bone-resorption and has been shown to directly and indirectly prevent proliferation, induce apoptosis, and inhibit metastasis of various types of cancer cells (Kuroda et al, 2003;Green, 2004;Santini et al, 2006). Bisphosphonates inhibit farnesyl pyrophosphate synthase, which is part of the mevalonate pathway.…”

mentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

“…16,17 In preclinical testing, zoledronic acid has been shown to be the most potent inhibitor of bone resorption compared to other bisphosphonates 18 and this potency is also reflected in the various antitumor activities investigated to date. Furthermore, zoledronic acid has shown synergistic induction of cancer cell apoptosis in vitro when combined with a variety of agents, e.g., with imatinib mesylate in leukemia cells 19 or in lung cancer cells, 20 with gemcitabine in prostate cancer cells, 21 with paclitaxel or tamoxifen 22,23 or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 24 in breast cancer cells and with dexamethasone in myeloma cells. 25 Other bisphosphonates investigated for synergistic cell death in combination with chemotherapeutic agents have shown either no effect (pamidronate with DTIC in melanoma cell lines) 26 or additive activity at best (ibandronate with taxanes in breast cancer cells).…”

mentioning

confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

View full text Add to dashboard Cite

We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

show abstract

The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate

Cited by 114 publications

References 41 publications

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

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

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Contact Info

Product

Resources

About