Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Räikkönen, Johanna; Mönkkönen, Hannu; Auriola, Seppo; Mönkkönen, Jukka

doi:10.1016/j.bcp.2009.10.003

Cited by 45 publications

(43 citation statements)

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“…The addition of GGPP but not FPP into ZOL-treated cells resulted in an almost complete inhibition of IPP accumulation through the down regulation of HMGCoA reductase in addition to rescuing small GTPases prenylation. 44) Similar results were also obtained with FLU-treated cells (Figs. 3A, B), where the addition of GGPP completely reversed FLU-induced antiproliferative effect.…”

Section: )supporting

confidence: 79%

“…The molecular mechanism of NBPs is usually due to the inhibition of FPP synthase and loss of signaling in the downstream pathway of small GTPases, such as Ras proteins. 16,43) Previous studies showed that a consequence of FPP synthase inhibition by ZOL is the accumulation of intracellular isopentenyl pyrophosphate (IPP), which leads to the formation of pro-apoptotic ATP analogue APPPI (triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl)ester) inducing apoptosis 44,45) (Fig. 5).…”

Section: )mentioning

confidence: 99%

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Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

Elsayed

Kobayashi

Kubota

et al. 2016

Biological & Pharmaceutical Bulletin

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Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5′-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU.Key words pancreatic cancer; zoledronic acid; fluvastatin; combination treatment; synergistic Pancreatic cancer is known to be the fifth leading cause of cancer-related mortality in Japan and considered to be one of the most aggressive malignancies. 1) Moreover, patients treated with surgical interventions usually develop tumor relapse and/or liver metastasis.2) Gene mutations, including K-ras, CDKN2A (p16), and TRP53, are often associated with pancreatic cancer.3) Previous studies have shown that blocking and/or depriving cells of K-ras may be a promising way to treat pancreatic cancer. 4,5) Although gemcitabine has been considered the standard care treatment for pancreatic cancer, 6) its clinical use remains limited. Therefore, the development of new therapeutic strategies is needed.The third-generation nitrogen bisphosphonates (NBPs) are currently considered a key therapy for the treatment of osteoclast-mediated bone resorption, bone metastasis, and malignant skeletal-related diseases. 7) NBPs have also shown direct antiproliferative and apoptotic effects on solid tumors [8][9][10][11][12] by inhibiting the farnesyl pyrophosphate (FPP) synthase, a key regulatory enzyme in the mevalonate pathways.13) Impairing the prenylation of small guanosine 5′-triphosphate (GTP) proteins such as Ras, Rab, Rho, and Rac by FPP synthase inhibitors may lead to the loss of many cellular processes. 14)Zoledronic acid (ZOL) is one of the most potent drugs owing to its direct and indirect antitumor effects, 15) and it has been effectively used for the treatment of several cancer cell types...

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Section: )supporting

confidence: 79%

Section: )mentioning

confidence: 99%

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

Elsayed

Kobayashi

Kubota

et al. 2016

Biological & Pharmaceutical Bulletin

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“…The mevalonate pathway is a biosynthetic pathway responsible for the production of cholesterol and isoprenoid lipids, particularly the farnesyl-and geranylpyrophosphates which are required for the prenylation of small GTP proteins that play crucial roles in signalling pathways controlling cell growth. Inhibition of the mevalonate pathway has been proposed as being the fundamental molecular mechanism of many of the observed anti-cancer effects of N-BPs, such as ZA, both in vitro and in vivo [ 12 ] . After FPPS inhibition by N-BPs, the pathway is blocked and inhibition of protein prenylation occurs as a result of the lack of FPP and GGPP enzymes.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone‐refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A

et al. 2012

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E 11 4 7 OBJECTIVES• To investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the serine/threonine protein phosphatase inhibitors calyculin A (CA) and okadaic acid (OA) in hormone and drug refractory prostate cancer cells, PC-3 and DU-145.• To discover the effect of these combination treatments on phosphatase 1 (PP1) and PP2A protein expression levels in prostate cancer cells. MATERIALS AND METHODS• An XTT cell viability assay was used to determine cytotoxicity.• Apoptosis was evaluated by enzymelinked immunosorbent assay (ELISA) using a Cell Death Detection ELISA Plus Kit and verifi ed by measuring caspase 3/7 enzyme activity.• The PP1 and PP2A enzyme activities were evaluated by serine/threonine phosphatase ELISA and expression levels of PP1 and PP2A proteins were then re-assessed by Western blot analysis. RESULTS• Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis compared with any agent alone

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“…2), suggesting that ZOL induced apoptosis at least in part. Pandha et al and Ullén et al reported that ZOL induced apoptotic cell death in a caspase-dependent manner; however, they did not examine the involvement of the mevalonate pathway (20,21), although there have been reports suggesting that the mevalonate pathway is important for the mechanisms of cell death induced by bisphosphonates in multiple myeloma, prostate cancer and breast cancer (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Involvement of the mevalonate pathway in the antiproliferative effect of zoledronate on ACHN renal cell carcinoma cells

Okamura

2012

Oncol Rep

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Abstract. Renal cell carcinoma (RCC) has been shown to be resistant to chemotherapy and radiotherapy. In order to examine the potential of zoledronate (ZOL), a bisphosphonate, as an anticancer agent, we investigated the effects of ZOL on RCC cells and the involvement of the mevalonate pathway in antiproliferative effects, as well as the effects of ZOL administration on mice inoculated with RCC. ACHN cells were used and cell viability was measured via intra cellular reductase activity. Chromatin condensation was detected by Hoechst 33342 staining. Proteins were detected by western blot analysis. Tumor volume was measured bidimensionally in mice inoculated with ACHN cells after vehicle or ZOL subcutaneous administration. ZOL exhibited antiproliferative effects with an IC 50 value of 2.29±0.53 µM in ACHN cells and chromatin condensation was observed when treated with ZOL. Farnesol (FOH) and geranylgeraniol (GGOH), precursors of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, exhibited potency to rescue cells treated with ZOL. Additionally, Ras and RhoA proteins located in the membrane fraction decreased when treated with ZOL and recovered by FOH or GGOH treatment, suggesting that ZOL inhibited the mevalonate pathway, thereby suppressing the translocation of prenylated Ras and RhoA proteins to membrane fractions. An in vivo study showed the inhibitory potential of ZOL on tumor growth in mice without changes in body weight. Our study showed that ZOL could be useful as an anticancer agent for the treatment of RCC, and the mevalonate pathway could be an efficient target for novel therapeutic agents against RCC. IntroductionRenal cell carcinoma (RCC) can be resistant to chemotherapy and radiotherapy, making nephrectomy the most effective treatment (1). Although nephrectomy can be expected to cure patients without metastatic involvement, the 5-year survival rate of those with metastasis is <10%. In addition, recent advances in drug development have allowed us to use novel agents for RCC targeting the cancer-specific pathway, such as bevacizumab, sorafenib and sunitinib (2-4). Although they prolonged overall survival in patients with advanced RCC, the effect was still insufficient; thus, it is necessary to discover novel chemotherapy for RCC. There have been studies by us and other groups, showing the possibility of other targets to treat RCC (5-7).Bisphosphonates have been widely used for the treatment of bone disease with potent antiresorptive activity, especially nitrogen-containing bisphosphonates, including aldendronate (ALN), risedronate (RISE), and zoledronate (ZOL), which have been characterized to have strong inhibitory effects on the mevalonate pathway, thereby inhibiting the prenylation of Ras and Rho inducing cell apoptosis (8,9). ZOL is the most potent nitrogen-containing bisphosphonate and it is widely used for bone diseases caused by metastasis of breast, prostate, bladder, and renal cancer (10,11). In addition, ZOL has been shown to have cytotoxic effects on cancer cells, including multiple myelom...

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Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Cited by 45 publications

References 45 publications

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone‐refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A

Involvement of the mevalonate pathway in the antiproliferative effect of zoledronate on ACHN renal cell carcinoma cells

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