Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Mani, Jens; Vallo, Stefan; Barth, Katja; Makarević, Jasmina; Juengel, Eva; Bartsch, Georg; Wiesner, Christoph; Haferkamp, Axel; Blaheta, Roman A.

doi:10.1038/pcan.2012.9

Cited by 23 publications

(12 citation statements)

References 33 publications

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“…In addition to the skeletal benefits of N-BPs, recent pre-clinical studies have shown that they can suppress the proliferation of various types of cancer cells, including prostate (Iguchi et al, 2010; Mani et al, 2012), breast (Räikkönen et al, 2010; Dedes et al, 2012), and colorectal (Notarnicola et al, 2004) cancers, human glioblastoma (Cimini et al, 2011), and multiple myeloma (MM). Higher expression of hFPPS has been observed in human prostate cancer tissues (as compared to controls), suggesting an association between prenylation and disease progression (Todenhöfer et al, 2013).…”

Section: Overview Of the Human Fpps Ggpps And Sqs As Therapeutic Tamentioning

confidence: 99%

Human isoprenoid synthase enzymes as therapeutic targets

et al. 2014

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In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.

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Section: Overview Of the Human Fpps Ggpps And Sqs As Therapeutic Tamentioning

confidence: 99%

Human isoprenoid synthase enzymes as therapeutic targets

et al. 2014

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“…According to previous studies, it is controversial whether ZOL affects cyclin and cyclin-dependent kinase inhibitor expression levels in cancer cells (14,(25)(26)(27). To elucidate the mechanism by which ZOL causes S-phase arrest in CNE-2 and HNE-1 cells, the expression status of cyclins A, B, D1 and E, as well as p21 CIP1 and p27…”

Section: Zol Plus Ir Elevates the Expression Levels Of S-and M-phase mentioning

confidence: 99%

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

Wang

et al. 2017

Oncology Letters

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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...

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“…In our hands, ZA toxicity was already significant after 48 h culture at 20 μM, regardless of LA cotreatment. In a previous study [19], the toxicity of ZA was observed at lower concentrations probably because of different experimental conditions. It is of note that, in vivo, the effective local concentrations of bisphosphonates at sites of active bone resorption are much higher than serum levels and may reach up to 10 −3 M in the resorption lacunae [27].…”

Section: Discussionmentioning

confidence: 99%

“…Drugs were added to culture medium, alone or in combination, testing various concentrations from 2.5 μM to 50 μM (ZA) [19] and 0.5 μM to 100 μM (LA) [23] for 24-96 h, according to protocols.…”

Section: Proliferation Assaymentioning

confidence: 99%

Zoledronic Acid and Leuprorelin Acetate, Alone or in Combination, Similarly Reduce Proliferation and Migration of Prostate Cancer Cells In Vitro

Mognetti¹,

Montagna²,

Perrelli³

et al. 2014

International Journal of Medical Biology

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We studied the effects of zoledronic acid (ZA) and leuprorelin acetate (LA) separately and combined on a human cell line derived from a bone metastasis of prostatic adenocarcinoma (PC3). In particular, we focused on the effects that drugs given singularly or in association may play on tumor evolution and metastatization. Cell proliferation, 2D-and 3D-migration were studied in basal conditions and under attractive stimuli exerted by bone marrow mesenchymal stem cells (BM-MSC). Either drug decreased PC3 proliferation, though ZA was much more cytotoxic than LA. However, LA cytotoxic concentrations are higher than those usually reached in vivo. Subtoxic concentration of either drug inhibited migration especially under BM-MSC medium stimuli via an Akt-dependent mechanism. The capability of either drug to inhibit cellular migration is in line with their well-known effect in limiting metastatization. Intriguingly, no additive effect on the antiproliferative activity or in hindering migration is observed when the drugs are administered concomitantly, compared to the effects of each drug alone.

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Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Cited by 23 publications

References 33 publications

Human isoprenoid synthase enzymes as therapeutic targets

Human isoprenoid synthase enzymes as therapeutic targets

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

Zoledronic Acid and Leuprorelin Acetate, Alone or in Combination, Similarly Reduce Proliferation and Migration of Prostate Cancer Cells In Vitro

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