pitavastatin and Breast-Neoplasms

Fighting breast tumors mandates finding different agents devoid of chemotherapy side effects. Repurposing existing drugs, such as statins, presents a promising avenue for the development of novel cancer therapeutics. Based on the different effects of statin members, this study aims to evaluate the effect of two of the most promising lipophilic statins, Simvastatin and Pitavastatin, and their combination with a conventional chemotherapeutic regimen of doxorubicin and cyclophosphamide on breast cancer cells. MDA-MB-231 and MCF7 cell lines were used to analyze the effects of Pitavastatin and simvastatin in combination with doxorubicin/cyclophosphamide. Cell viability and cell cycle were analyzed and certain apoptosis-related genes such as Bax, Bcl2, and caspase-3, besides cyclin D1 were analyzed using qPCR. The viability of breast cancer cells decreased significantly after treatment with a doxorubicin/cyclophosphamide combination in the presence of Pitavastatin or simvastatin compared with dual doxorubicin/cyclophosphamide with a higher effect in MDA-MB-231 cells than MCF7. In MDA-MB-231, The triple combination of Pitavastatin or simvastatin with doxorubicin/cyclophosphamide resulted in an increase in the expression levels of apoptotic markers than treatment with doxorubicin/cyclophosphamide combination (Bax (p-value = 0.09& 0.02, respectively), Bax/Bcl2 ratio (p-value = 0.0002& <0.0001, respectively)). However, the increase in caspase3 wasn't significant (p-value = 0.45& 0.09, respectively). Moreover, the expression of cyclin D1 decreased (p-value = 0.0002& <0.0001, respectively) and the cell cycle was arrested in the G1 phase. Combination of Pitavastatin or simvastatin with doxorubicin/ cyclophosphamide may induce apoptosis in breast cancer cells via upregulation of the Bax/Bcl2 pathway, potentially providing a promising new therapeutic strategy for breast cancer.

Topics: Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cyclin D1; Cyclophosphamide; Doxorubicin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Simvastatin

Bone is a frequent site of metastasis from breast cancer, and a desirable drug could suppress tumor growth as well as metastasis-linked bone loss. Currently, no drug is able to cure breast cancer-associated bone metastasis. In this study, we focused on statins that are known to inhibit cholesterol production and act as antitumor agents. After an initial potency screening of 7 U.S. Food and Drug Administration-approved statins, we examined pitavastatin as a drug candidate for inhibiting tumor and tumor-induced bone loss.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Line; Cell Line, Tumor; Down-Regulation; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Mevalonic Acid; Mice; Mice, Inbred BALB C; Osteoblasts; Quinolines; RAW 264.7 Cells; Volatile Organic Compounds

Our previous results indicated significant tumor-suppressive effects of different statins in rat mammary carcinogenesis. The purpose of this experiment was to examine the chemopreventive effects of Pitavastatin alone and in combination with the pineal hormone melatonin in the model of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats. Pitavastatin was administered dietary (10mg/kg) and melatonin in an aqueous solution (20μg/ml). Chemoprevention began 7 days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Compared to controls, Pitavastatin alone reduced average tumor volume by 58% and lengthened latency by 8 days; on the other hand, the drug increased tumor frequency by 23%. Combined administration of Pitavastatin with melatonin decreased tumor frequency by 23%, tumor volume by 44% and lengthened tumor latency by 5.5 days compared to control animals. The analysis of carcinoma cells showed significant increase in caspase-3 expression in both treated groups and a tendency of increased caspase-7 expression after Pitavastatin treatment alone. Significant expression decrease of Ki67 was found in carcinoma cells from both treated groups. Compared to control carcinoma cells, Pitavastatin alone increased VEGF expression by 41%, however melatonin totally reversed its undesirable effect. Pitavastatin combined with melatonin significantly increased femur compact bone thickness in animals. Pitavastatin alone decreased plasma triglycerides and total cholesterol levels, however it significantly increased levels of glucose. In summary, our results show a partial antineoplastic effect of Pitavastatin combined with melatonin in the rat mammary gland carcinoma model.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Melatonin; Quinolines; Rats

The aim of the present study was to provide new mechanistic insight into the effect of pitavastatin at low dose on NF-kappaB activated by TNF-alpha in the human breast cancer cell line (MCF-7). We found that treatment of MCF-7 with 1 microM pitavastatin inhibited the proliferation and suppressed the nuclear expression of NF-kappaB p65 induced by TNF-alpha with Western blotting. Furthermore, EMSA showed that pitavastatin significantly reduced the DNA binding activity of NF-kappaB induced by TNF-alpha. Subsequently, luciferase assay revealed that pitavastatin (1 microM) inhibited the transcriptional activity of the NF-kappaB promoter, which was clearly related to the HMG-CoA reductase activity because addition of mevalonic acid (MEV) could elevate the NF-kappaB activity. Moreover, the Rho kinase inhibitor Y27632 abolished the effect of pitavastatin on NF-kappaB activity. Finally, the addition of TNF-alpha significantly increased IL-6 protein production, which was suppressed by the addition of pitavastatin. These results suggest that pitavastatin at low dose (1 microM) inhibits NF-kappaB activation and decreases IL-6 production induced by TNF-alpha. It is dependent on Rho kinase pathway in human breast cancer cells.

Topics: Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; DNA, Neoplasm; Humans; Interleukin-6; Intracellular Signaling Peptides and Proteins; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Quinolines; rho-Associated Kinases; Transcription Factor RelA; Transcription, Genetic; Tumor Necrosis Factor-alpha