Anti-inflammatory Effect of Pitavastatin on NF-.KAPPA.B Activated by TNF-.ALPHA. in Hepatocellular Carcinoma Cells

Wang, Juyong; Tokoro, Takashi; Higa, Susumu; Kitajima, Isao

doi:10.1248/bpb.29.634

Cited by 32 publications

(31 citation statements)

References 37 publications

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“…activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells ABEER AL-QATATI 1 and SAEB ALIWAINI On a molecular level, pitavastatin treatment has been demonstrated to upregulate the cell cycle regulator p21 and to inhibit nuclear factor-κB (NF-κB) in different tumour cells, which resulted in cell cycle arrest and apoptosis (13,14). Finally, in glioma cells, autophagic cell death was demonstrated to be a potential mechanism of pitavastatin-induced cytotoxicity by also resulting in the inhibition of NF-κB (15).…”

Section: Combined Pitavastatin and Dacarbazine Treatmentmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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Abstract. Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anticancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. IntroductionMelanoma is a particularly aggressive skin cancer and its incidence is increasing faster than any other cancer worldwide (1). At present, the 10-year survival rate of patients diagnosed with advanced (stage IV) metastatic melanoma is <10% (2), which highlights the importance of early detection and treatment. The Food and Drug Administration approved the chemotherapeutic agent dacarbazine (DTIC) for the treatment of metastatic melanoma in 1975, and it remains the only licensed chemotherapeutic agent in use today (1). DTIC is a methylating agent which causes DNA damage, cell cycle arrest and apoptosis. Despite this, only 2% of all patients with metastatic melanoma receiving this treatment demonstrate a significant response and only 11.2% demonstrate a partial response (3). Resistance to DTIC has been associated with the upregulation of pro-survival signals and anti-apoptotic molecules in cancer cells. Despite its moderate effects, DTIC continues to be the standard treatment for metastatic melanoma as no other chemotherapeutic treatment has been demonstrated to have a significantly increased chance of survival when compared with DTIC (4,5). Provided the limited efficacy of the current metastatic melanoma chemotherapies in addition to the increasing incidence of melanoma cases, there appears to be a need for the development of more effective treatment strategies.Statins are a group of drugs commonly used for the reduction of cholesterol levels (6). They work by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a critical enzyme in the mevalonate pathway, which is responsible for cholesterol synthesis (6,7). In addition, statins have been de...

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Section: Combined Pitavastatin and Dacarbazine Treatmentmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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“…Furthermore, in multiple myeloma, CAM-DR is accompanied by increased geranylgeranylation of RhoA and activation of Rho kinase, whereas inhibition of this pathway can overcome drug resistance [155]. Geranylgeranylation is HMG-CoA-reductasedependent, and inhibition of HMG-CoA reductase suppresses the transcriptional activity of the NFkB promoter in hepatocellular carcinoma [188]. Similarly, in gastric cancer function neutralizing antibodies to v 3 inhibit cysteine-rich-61-mediated NFkB activation and thus cell invasiveness [189].…”

Section: Adhesion Associated Pathwaysmentioning

confidence: 99%

ANTI-ADHESION Evolves To a Promising Therapeutic Concept in Oncology

Schmidmaier¹,

Baumann²

2008

CMC

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Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.

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“…The nuclear fraction was prepared essentially as described by Wang et al [14]. The protein concentration was determined using the Bio-Rad protein assay reagent according to the manufacturer's instruction.…”

Section: Western Blot Analysis For Nf-kb Activation In Ammentioning

confidence: 99%

Effect of triterpene acids of Eriobotrya japonica (Thunb.) Lindl. leaf on inflammatory cytokine and mediator induction from alveolar macrophages of chronic bronchitic rats

Huang

Wang³

et al. 2007

Inflamm. res.

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Anti-inflammatory Effect of Pitavastatin on NF-.KAPPA.B Activated by TNF-.ALPHA. in Hepatocellular Carcinoma Cells

Cited by 32 publications

References 37 publications

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

ANTI-ADHESION Evolves To a Promising Therapeutic Concept in Oncology

Effect of triterpene acids of Eriobotrya japonica (Thunb.) Lindl. leaf on inflammatory cytokine and mediator induction from alveolar macrophages of chronic bronchitic rats

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