Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

Ciechomska, Iwona A.; Legat, Magdalena; Gołąb, Jakub; Wesołowska, Aleksandra; Kurzaj, Zuzanna; Maćkiewicz, Andrzej; Kamińska, Bożena

doi:10.1002/ijc.21153

Cited by 33 publications

(32 citation statements)

References 36 publications

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“…For example, calcineurin inhibitors are able to increase the phosphorylation of SOX9 and thus its translocation to the nucleus (27). Interestingly, a new calcineurin inhibitor without immunomodulatory effects has shown promising results in treating melanomas (28). Deacetylase inhibitors can increase SOX9 expression not only in chondrocytes but also in sarcomas (29,30).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Passeron¹,

Valencia²,

Namiki³

et al. 2009

J. Clin. Invest.

104

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Treatments for primary and metastatic melanomas are rarely effective. Even therapeutics such as retinoic acid (RA) that are successfully used to treat several other forms of cancer are ineffective. Recent evidence indicates that the antiproliferative effects of RA are mediated by the transcription factor SOX9 in human cancer cell lines. As we have previously shown that SOX9 is expressed in normal melanocytes, here we investigated SOX9 expression and function in human melanomas. Although SOX9 was expressed in normal human skin, it was increasingly downregulated as melanocytes progressed to the premalignant and then the malignant and metastatic states. Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. Furthermore, SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 increased SOX9 expression and restored sensitivity to RA. Thus, combined treatment with PGD2 and RA substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. The results of our experiments targeting SOX9 provide insight into the pathophysiology of melanoma. Further, the effects of SOX9 on melanoma cell proliferation and RA sensitivity suggest the encouraging possibility of a noncytotoxic approach to the treatment of melanoma.

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Section: Discussionmentioning

confidence: 99%

Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Passeron¹,

Valencia²,

Namiki³

et al. 2009

J. Clin. Invest.

104

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“…In our experiments, CsA alone (0.1 -2 mM for 5 or 24 h depending on cell line) caused no PARP inactivation. Importantly, several in vitro studies have shown that CsA alone can induce apoptosis (PARP inactivation) although at much higher concentrations (30 -60 mM) (Pyrzynska et al, 2002;Ciechomska et al, 2005). The in vitro data on the combination of IT and CsA encouraged us to examine the effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo

2009

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BACKGROUND: The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human-anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious. METHODS: We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats. RESULTS: The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented. CONCLUSION: The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients.

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“…CsA is a well-known inhibitor of peptidylprolyl isomerase activity of CypA and has been studied in lung cancer, mainly in the context of chemotherapy regimens via its inhibition of the P-glycoprotein multidrug resistance protein (31)(32)(33). It has been shown to induce apoptosis in cancer cells, such as retinoblastoma and melanoma, but the exact mechanism has not been elucidated (34)(35)(36). CsA has several drawbacks as a therapeutic agent (i.e., through ''off-target'' effects-CsA is a potent immunosuppressant through inhibition of the calcineurin/nuclear factor of activated T-cell pathway in T cells, and by effects on transforming growth factor h-CsA has been shown to cause tumor progression in non-small-cell lung cancer; ref.…”

Section: Discussionmentioning

confidence: 99%

Stable RNA Interference–Mediated Suppression of Cyclophilin A Diminishes Non–Small-Cell Lung Tumor Growth In vivo

Howard

Furumai²,

Campa

et al. 2005

Cancer Research

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Cyclophilin A (CypA) was recently reported to be overexpressed in non-small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer. (Cancer Res 2005; 65(19): 8853-60)

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Cyclosporine A and its non-immunosuppressive derivative NIM811 induce apoptosis of malignant melanoma cells inin vitro andin vivo studies

Cited by 33 publications

References 36 publications

Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid

Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo

Stable RNA Interference–Mediated Suppression of Cyclophilin A Diminishes Non–Small-Cell Lung Tumor Growth In vivo

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