Antiproliferative and Apoptosis-Inducing Effects of Lipophilic Vitamins on Human Melanoma A375 Cells in Vitro

Ishibashi, Mai; Arai, Mariko; Tanaka, Sachiko; Onda, Kenji; Hirano, Toshihiko

doi:10.1248/bpb.35.10

Cited by 31 publications

(26 citation statements)

References 23 publications

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“…Notably, whilst DTIC treatment (40 µM) did not induce apoptosis, combined pitavastatin-DTIC treatment resulted in significant levels of apoptosis as evidenced by the increased level of apoptosis markers, cleaved PARP and active caspase 3, as well as annexin V staining. The results of the present study are in agreement with a number of studies which demonstrate that high concentrations of DTIC are necessary to induce apoptosis in melanoma cells (19,32,36). Whilst there has been insufficient research to determine which type of apoptosis is induced by DTIC, sensitization to the intrinsic apoptotic pathway has been revealed to augment DTIC-induced melanoma tumour cell death (37).…”

Section: Discussionsupporting

confidence: 91%

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: Discussionsupporting

confidence: 91%

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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“…245,257 It has been reported that 1,25(OH) 2 D3 induces apoptosis of WM1341 melanoma, but not MeWo cells. 244 Therefore, it is possible that the pro-apoptotic activity of 1,25(OH) 2 D3 depends on cell-type-specific factors as recently described in the gastric cancer cell line HGC-27 (see recent review ref.…”

Section: Vitamin D and Experimental Models Of Melanomamentioning

confidence: 99%

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Slominski

Brożyna

Żmijewski

et al. 2017

Laboratory Investigation

116

128

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Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.

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“…Subsequently, Newton-Bishop and colleagues in a UK study of 872 melanoma patients (5) reported that serum vitamin D levels were higher among those with better overall survival, and Rosso and colleagues in a European study of 260 melanoma patients (6) found that melanoma patients with more sunny vacations prior to diagnosis had better melanoma-specific survival. Laboratory studies have shown that vitamin D suppresses tumor proliferation (7) and suggest that increased vitamin D levels might keep a melanoma “in check”. To test the hypothesis that increased sun exposure prior to diagnosis is associated with improved survival from melanoma, we evaluated measures of solar UVR exposure prior to diagnosis in 3,578 incident melanoma patients in the Genes, Environment and Melanoma study (GEM), an international, population-based study (8).…”

Section: Introductionmentioning

confidence: 99%

Sun Exposure and Melanoma Survival: A GEM Study

Berwick

Reiner

Paine

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background We previously reported a significant association between higher ultraviolet radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure prior to diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information. Methods We conducted a multi-center, international population-based study in four countries – Australia, Italy, Canada and the United States – with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient UVB dose, histological solar elastosis and season of diagnosis. Results Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in one year within 10 years of diagnosis was inversely associated with survival; solar elastosis – a measure of lifetime cumulative exposure – was not. Additionally, none of the intermittent exposure measures – water related activities and sunny holidays - were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival. Conclusion Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure prior to diagnosis is associated with greater melanoma-specific survival. Impact This study adds to the evidence that sun exposure prior to melanoma diagnosis has little effect on survival with melanoma.

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Antiproliferative and Apoptosis-Inducing Effects of Lipophilic Vitamins on Human Melanoma A375 Cells in Vitro

Cited by 31 publications

References 23 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

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Sun Exposure and Melanoma Survival: A GEM Study

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