Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

Rae, Colin; Haberkorn, Uwe; Babich, John W.; Mairs, Robert J.

doi:10.1667/rr14173.1

Cited by 34 publications

(40 citation statements)

References 57 publications

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“…PC3 cells are p53 non-functional, whereas LNCaP cells are p53 wild-type (Carroll et al 1993). As demonstrated here and previously (Rae et al 2015), the cell cycle distribution differs between PC3 and LNCaP cells after irradiation. Cell cycle arrest in G 2 /M phase was observed in both cell lines 6 h after irradiation.…”

Section: Discussionsupporting

confidence: 82%

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Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

Rae

Mairs

2016

International Journal of Radiation Biology

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Purpose: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. Although ionizing radiation is used to treat localized and metastatic prostate cancer, the most efficient use of radiotherapy is yet to be defined. Our purpose was to determine in vitro the potential benefit to be gained by combining radiation treatment with cytotoxic drugs. Materials and methods: Inhibitors of DNA repair and heat shock protein 90 and an inducer of oxidative stress were evaluated in combination with X-radiation for their capacity to reduce clonogenic survival and delay the growth of multicellular tumor spheroids. Results: Inhibitors of the PARP DNA repair pathway, olaparib and rucaparib, and the HSP90 inhibitor 17-DMAG, enhanced the clonogenic cell kill and spheroid growth delay induced by X-radiation. However, the oxidative stress-inducing drug elesclomol failed to potentiate the effects of X-radiation. PARP inhibitors arrested cells in the G 2 /M phase when administered as single agents or in combination with radiation, whereas elesclomol and 17-DMAG did not affect radiation-induced cell cycle modulation. Conclusion: These results indicate that radiotherapy of prostate cancer may be optimized by combination with inhibitors of PARP or HSP90, but not elesclomol. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 82%

“…It is possible that the combination of radiation with radiosensitizing drugs increased the induction of apoptosis, similar to the radiosensitizing effect of the fatty acid inhibitor C75 (Rae et al 2015). The response to drugs or radiation may also be influenced by the p53 status of the cells.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

Rae

Mairs

2016

International Journal of Radiation Biology

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“…According to previous studies on tumor proliferation, FASN may contribute to the generation of tumor cell membranes (43). Therefore, FASN inhibitors such as C75 and orlistat are promising potential anti-cancer drugs for the prevention and/or treatment of a variety of cancers such as cervical, prostate, leukemia and colon cancer (44)(45)(46). It is essential to identify more effective FASN inhibitors that may be applied practically as chemotherapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

Patuletin induces apoptosis of human breast cancer SK‑BR‑3 cell line via inhibiting fatty acid synthase gene expression and activity

Zhu

Wang

et al. 2017

Oncol Lett

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Abstract. Fatty acid synthase (FASN) is a key enzyme involved in fatty acid biosynthesis and serves an important role in breast cancer development. The aim of the present study was to investigate the effects of patuletin on the gene expression and activity of FASN in the human breast cancer SK-BR-3 cell line, and the apoptotic effects of patuletin to breast cancer cells. Quantitative reverse transcription polymerase chain reaction, western blotting and intracellular FASN activity assays were used to evaluate FASN gene expression, protein expression and activity in patuletin-treated SK-BR-3 cells. MTT assays and flow cytometry were used to measure cell growth and cell apoptosis, respectively, following patuletin treatment. As a result, it was demonstrated that patuletin dose-dependently reduces FASN expression and intracellular activity in human breast cancer cells, and induces apoptosis in FASN over-expressing SK-BR-3 cells. Notably, apoptosis is associated with the reduction of intracellular FASN activity. The present study demonstrates that patuletin may be considered as a novel natural inhibitor of FASN, may induce anti-proliferative and pro-apoptotic effects in certain human breast cancer cells and may be useful for preventing and/or treating human breast cancer. IntroductionFatty acid synthase (FASN) is a multi-enzyme that catalyzes the de novo synthesis of palmitate (C16:0, a long-chain saturated fatty acid) from acetyl-CoA and malonyl-CoA, in the presence of NADPH (1). FASN is not only a key factor in the role of fatty acid biosynthesis for energy storage (2,3), but also its expression level increases significantly in adipose tissues and a variety of human carcinomas, including liver, breast, prostate, lung, endometrium, ovary, colon and pancreatic cancer (4-13). This prominent difference of FASN expression between normal and neoplastic tissues makes FASN a potential diagnostic tumor marker (14).Breast cancer is the most common type of cancer and a leading cause of cancer-associated mortalities among females, with a common feature of abnormal cell apoptosis in its development (15). In addition, high levels of FASN expression has been demonstrated to be associated with poor clinical outcome in breast carcinomas, suggesting that FASN expression and tumor aggressiveness are closely associated (4,16). It was identified that obesity may serve a crucial role in the incidence and progression of breast cancer (17). According to the close association between FASN, obesity and breast cancer, the studies of FASN inhibitors have indicated their role as targets for chemotherapy in breast cancer and a novel strategy for antineoplastic intervention (18). In fact, previous studies demonstrated that certain synthetic and natural FASN inhibitors, including C75, desoxyrhaponticin, rhaponticin and α-mangostin may lead to selective cytotoxicity in FASN over-expressing cancer cell lines (18)(19)(20). This result suggested again that the pharmacological inhibition of FASN may represent a potential target for drug development.In...

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“…We have previously demonstrated that C75 was cytotoxic to prostate cancer cell lines (PC3 and LNCaP), decreased survival of PC3 clonogens, and inhibited the growth of multicellular spheroids composed of LNCaP cells 6. Crucially, C75 enhanced the clonogenic kill and spheroid growth delay induced by experimental radiotherapy in a synergistic manner characteristic of a radiosensitizer.…”

Section: Introductionmentioning

confidence: 99%

“…However, that study used orlistat, which is poorly soluble and has an extremely low oral bioavailability,15 thus limiting its clinical application. Radiosensitization of cancer cells was also achievable using C75 6. However, it is possible that the racemic mixture of C75 may modulate the activity of CPT‐1 activity, which is responsible for its undesirable effects on body weight and appetite in patients with cancer 11.…”

Section: Introductionmentioning

confidence: 99%

Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75

2016

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The elevated activity of fatty acid synthase has been reported in a number of cancer types. Inhibition of this enzyme has been demonstrated to induce cancer cell death and reduce tumor growth. In addition, the fatty acid synthase inhibitor drug C75 has been reported to synergistically enhance the cancer‐killing ability of ionizing radiation. However, clinical use of C75 has been limited due to its producing weight loss, believed to be caused by alterations in the activity of carnitine palmitoyltransferase‐1. C75 is administered in the form of a racemic mixture of (−) and (+) enantiomers that may differ in their regulation of fatty acid synthase and carnitine palmitoyltransferase‐1. Therefore, we assessed the relative cancer‐killing potency of different enantiomeric forms of C75 in prostate cancer cells. These results suggest that (−)‐C75 is the more cytotoxic enantiomer and has greater radiosensitizing capacity than (+)‐C75. These observations will stimulate the development of fatty acid synthase inhibitors that are selective for cancer cells and enhance the tumor‐killing activity of ionizing radiation, while minimizing weight loss in cancer patients.

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Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

Cited by 34 publications

References 57 publications

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

Patuletin induces apoptosis of human breast cancer SK‑BR‑3 cell line via inhibiting fatty acid synthase gene expression and activity

Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75

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