Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

Knight, Louise A.; Kurbacher, Christian M.; Glaysher, Sharon; Fernando, Augusta; Reichelt, Ralf; Dexel, S.; Reinhold, Uwe; Cree, Ian A.

doi:10.1186/1471-2407-9-38

Cited by 28 publications

(16 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…40) Moreover, it was reported that a combination of ZOL and FLU had a high safety margin and possessed no potential for drug interactions when used with other cancer cell lines. 30,41,42) There are controversies over the inhibition mechanism of the mevalonate pathway by NBPs and statins. 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.…”

Section: )mentioning

confidence: 99%

“…26,27) Several studies have focused on the cytotoxic effects of fluvastatin (FLU), which inhibits cell proliferation, suppresses angiogenesis, and triggers apoptosis. 28,29) Although the antitumor effect of the combination of ZOL and FLU has been investigated in other types of cancer, 30,31) it was not reported whether this combination treatment has a synergistic cytotoxic effect on pancreatic cancer cells or not. We evaluated the synergistic antiproliferative effect on two types of pancreatic cancer cell lines in vitro.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: )mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…ATP tumour chemosensitivity assays have been recommended to assess the viability of chemotherapy for the treatment of primary recurrent platinum-resistant epithelial ovarian cancer [421][422][423][424][425][426]. A combination of zoledronic acid and fluvastatin has been claimed to have activity against ovarian (and breast) cancer based on this assay [427]. A 2 receptor antagonism inhibits angiogenic activity of human ovarian cancer cells [428].…”

Section: Ovarian Cancermentioning

confidence: 99%

Purinergic signalling and cancer

Burnstock

Virgilio

2013

Purinergic Signalling

267

265

View full text Add to dashboard Cite

Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.

show abstract

“…The assay is particularly helpful for the in vitro design of new combinations, particularly where there was a molecular hypothesis to test. For instance, we were able to show that the effect of mevalonate pathway inhibitors was limited, but that they enhanced the effect of N-bisphosphonates, probably via the production of metabolites not normally present in the cell (11). We have most recently used the assay to show that EGFR and PI3K blockade is synergistic in ovarian cancer cells (Glaysher et al, unpublished data).…”

Section: The Atp-tcamentioning

confidence: 92%

Designing personalised cancer treatments

Cree

2013

Journal of Controlled Release

View full text Add to dashboard Cite

The concept of personalized medicine for cancer is not new. It arguably began with the attempts by Salmon and Hamburger to produce a viable cellular chemosensitivity assay in the 1970s, and continues to this day. While clonogenic assays soon fell out of favour due to their high failure rate, other cellular assays fared better and although they have not entered widespread clinical practice, they have proved to be very useful research tools. For instance, the ATP-based chemosensitivity assay was developed in the early 1990s and is highly standardised. It has proved useful for evaluating new drugs and combinations, and in recent years has been used to understand the molecular basis of drug resistance and sensitivity to anti-cancer drugs.Recent developments allow unparalleled genotyping and phenotyping of tumours, providing a plethora of targets for the development of new cancer treatments. However, validation of such targets and new agents to permit translation to the clinic remains difficult. There has been one major disappointment in that cell lines, though useful, do not often reflect the behaviour of their parent cancers with sufficient fidelity to be useful. Low passage cell lines -either in culture or xenografts are being used to overcome some of these issues, but have several problems of their own. Primary cell culture remains useful, but large tumours are likely to receive neo-adjuvant treatment before removal and that limits the tumour types that can be studied. The development of new treatments remains difficult and prediction of the clinical efficacy of new treatments from pre-clinical data is as hard as ever. One lesson has certainly been that one cannot buck the biology -and that understanding the genome alone is not sufficient to guarantee success. Nowhere has this been more evident than in the development of EGFR inhibitors. Despite overexpression of EGFR by many tumour types, only those with activating EGFR mutations and an inability to circumvent EGFR blockade have proved susceptible to treatment.The challenge is how to use advanced molecular understanding with limited cellular assay information to improve both drug development and the design of companion diagnostics to guide their use. This has the capacity to remove much of the guesswork from the process and should improve success rates.

show abstract

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

Cited by 28 publications

References 22 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

Purinergic signalling and cancer

Designing personalised cancer treatments

Contact Info

Product

Resources

About