Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition

Ahmed, Tamer A.; Hayslip, John; Leggas, Markos

doi:10.1016/j.leukres.2014.09.002

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…These inhibitors serve as promising, effective antineoplastic agents for the treatment of malignant oral tumors, and are characterized by low cytotoxicity, strong specificity, a long duration of action, high solubility and metabolic stability, all of which contribute to their anti-tumor effects. At present, certain inhibitors have been used in phase I or phase II clinical trials and achieved promising effects (55).…”

Section: Regulation Of the Mapk Signaling Pathway For Targeted Oral Cmentioning

confidence: 99%

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

et al. 2017

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Abstract. The mitogen-activated protein kinase (MAPK) signaling pathway is associated with tumor cell proliferation, differentiation, apoptosis, angiogenesis, invasion and metastasis. The present review assesses the involvement of the MAPK signaling pathway in oral cancer progression and invasion based on analysis of individual sub-pathways and their mechanisms of action. The regulation of this pathway for targeted oral cancer therapy is explored and the challenges confronting this, as well as corresponding potential solutions, are discussed. Exploring this pathway with an emphasis on its components, subfamilies, sub-pathways, interactions with other pathways and clinical practice modes may improve oral cancer treatment.

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Section: Regulation Of the Mapk Signaling Pathway For Targeted Oral Cmentioning

confidence: 99%

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

et al. 2017

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“…Both simvastatin and CID-1067700 significantly reduced actin filament staining as demonstrated by the decreased MFI in both single agent and combination treatments and affected the morphological appearance and structure of OCCC cells, while also inhibiting migration, suggesting that both drugs exert their activity by inhibiting Rho GTPases. Adding GGPP to simvastatin rescued all cell lines from cell death, further suggesting that simvastatin interferes with small GTPases [19], but the caspase inhibitor Z-VAD-FMK only rescued carboplatin-induced cell death in JHOC-5 cells, strengthening the notion of differences in the mode of cell death. The effect upon invasive potential was not investigated in this study.…”

Section: Discussionmentioning

confidence: 74%

“…Statins inhibit the conversion of HMG-CoA into mevalonic acid, and thus inhibit the synthesis of the isoprenoid intermediates farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), the latter of which is required by Rho GTPases for localization to the membrane [ 19 ]. Although debated, some evidence for increased survival in EOC patients after statin treatment has been shown, while the effect upon EOC risk is unclear [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin is a potential candidate drug in ovarian clear cell carcinomas

Arildsen

Hedenfalk

2020

Oncotarget

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Ovarian clear cell carcinomas (OCCC) constitute a rare subtype of epithelial ovarian cancer, lacking efficient treatment options. Based on previous studies, we assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer (HGSOC) cell line, Caov3. We used the Rho GTPase interfering drug CID-1067700 as a control. All OCCC cell lines were more sensitive to single-agent simvastatin than the HGSOC cells, while all cell lines were less sensitive to CID-1067700 than to simvastatin. Combinations of carboplatin and simvastatin were generally antagonistic. Most treatments inhibited migration, while only simvastatin and CID-1067700 also disrupted actin organization in the OCCC cell lines. All treatments induced a G1 arrest in JHOC-5 and TOV-21G cells. Treatments with simvastatin consistently reduced c-Myc protein expression in all OCCC cell lines and displayed evidence of causing both caspase-mediated apoptotic cell death and autophagic response in a cell line dependent manner. Differences between cell lines in response to the treatments were observed and such differences, including e. g. prior treatment, should be investigated further. Conclusively, simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.

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“…Further, downregulation of Mcl-1 expression has been shown by other statins such as lovastatin in myeloma plasma cells (van de Donk et al, 2003a) and malignant lymphocytes (van de Donk et al, 2003b). In addition, the combination of simvastatin and tipifarnib (a small molecule) in leukemia has been shown to induce apoptosis via downregulation of Mcl-1 (Ahmed et al, 2014). Finally, our findings showed that simvastatin-irinotecan combination upregulated GRP78 protein levels which was previously shown in leukemic cells (Xu and Villalona-Calero, 2002) and macrophages (Chen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1

Alqudah

Mansour

Mhaidat

2018

Saudi Pharmaceutical Journal

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Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in several cancer types including lung, colon, pancreas, breast, and prostate cancer. In this study we aimed to explore the potential role of simvastatin in enhancing irinotecan-induced apoptosis in prostate cancer cells. In addition, the underlying molecular mechanisms driving this potential effect of simvastatin were also explored. PC3 cells were treated with simvastatin, irinotecan or combination. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. Western blot was used for detection of protein expression. Results showed that simvastatin has a significant anti-proliferative activity on PC3 cells. Combined treatment of simvastatin with irinotecan exhibited a significant inhibition of PC3 cell growth compared to each treatment alone. Flow cytometry analysis showed that PC3 cell treatment with simvastatin and irinotecan combination demonstrated a remarkable increase in the percentage of apoptotic cells and those accumulated at G0/G1 phase when compared to each treatment alone. Moreover, induction of apoptosis was caspase-independent. Western blot showed that apoptosis was accompanied by upregulation of GRP-78 level and downregulation of Mcl-1 levels in a time-dependent manner. The results of this study demonstrated that combined treatment of simvastatin with chemotherapeutic agents such as irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis.

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Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition

Cited by 12 publications

References 38 publications

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

Simvastatin is a potential candidate drug in ovarian clear cell carcinomas

Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1

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