Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines

Tassone, Pierfrancesco; Forciniti, Stefania; Galea, Eulalia; Morrone, Giovanni; Turco, MC; Martinelli, Vincenzo; Tagliaferri, Pierosandro; Venuta, Salvatore

doi:10.1038/sj.leu.2401770

Cited by 125 publications

(79 citation statements)

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“…19 BP can induce apoptosis, inhibit cell cycle progression, and the proliferation in vitro of several types of cancer cells. [20][21][22][23][24][25][26][27] Synergy was also observed when BP were combined with other chemotherapeutic agents. 21,24,27,28 Zoledronate (ZOL), a third generation BP, was shown to prolong the survival of immunodeficient mice inoculated with an IMsensitive human CML cell line both alone and in combination with IM.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22][23][24][25][26][27] Synergy was also observed when BP were combined with other chemotherapeutic agents. 21,24,27,28 Zoledronate (ZOL), a third generation BP, was shown to prolong the survival of immunodeficient mice inoculated with an IMsensitive human CML cell line both alone and in combination with IM. 27 In the present study, we examined whether IM-resistant CML cells exhibit cross-resistance to ZOL, and whether the combination of IM and ZOL offers any advantage for elimination of these cells.…”

Section: Introductionmentioning

confidence: 99%

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Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

et al. 2005

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

et al. 2005

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“…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). 27 Anthracyclines such as doxorubicin and epirubicin are commonly used to manage early and metastatic breast cancer.…”

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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

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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...

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“…In addition to the potent antiresorptive effects of nitrogencontaining BPs, recent reports have also shown that these compounds induce antiproliferative and apoptotic effects in multiple myeloma cells in vitro (Shipman et al, 1997;Aparicio et al, 1998), may synergise with chemotherapeutic or biological agents (Tassone et al, 2000(Tassone et al, , 2002, and may offer clinical benefits (Dhodapkar et al, 1998;Berenson et al, 1998). A direct effect induced by BPs has also been demonstrated on tumour cells of nonhaematopoietic origin.…”

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Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro

et al. 2003

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Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21 ras pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21 ras . We found that ZOL induces growth inhibition (IC 50 :10 -50 mM) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/ activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21 ras signalling in cells exposed to ZOL and detected a reduction of p21 ras and Raf-1 content and functional downregulation of the terminal enzyme ERK/ MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21 ras . These findings might be relevant for expanding application of BPs in cancer treatment.

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Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines

Cited by 125 publications

References 23 publications

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells

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

Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro

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