Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

Sinha, Alok; Anand, Sanjay; Ortel, Bernhard; Chang, Yuchiao; Mai, Zhiming; Hasan, Tayyaba; Maytin, Edward V.

doi:10.1038/sj.bjc.6603273

Cited by 104 publications

(118 citation statements)

References 35 publications

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“…anand et al reported that methotrexate (Mtx) stimulated the accumulation of an intracellular photosensitizer, protoporphyrin Ⅸ, and enhanced the antitumor effect of PDT using 5-aminolaevulinic acid (ala), but that ala-PDt followed by Mtx yielded no enhancement in tumor cell lethality (42,43). in the present study, as shown in fig.…”

Section: Discussionsupporting

confidence: 48%

Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells

Maehara

Usuda

Ishizumi

et al. 2014

International Journal of Oncology

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Abstract. to identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDt) using the photosensitizer nPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. four human malignant mesothelioma cell lines (MSto-211H, H2052, H2452 and H28) were assayed using the WSt assay after treatment with pemetrexed and nPe6-PDt. the treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre-treatment enhanced the lethal effect of nPe6-PDt in the four malignant mesothelioma cell lines, but nPe6-PDt followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre-treatment did not enhance the intracellular accumulation of nPe6, which is one of the determinants of the antitumor effect of PDt. in nude mice injected with MSto-211H cells and then treated using a combination of pemetrexed and nPe6-PDt (10 mg/kg nPe6, 10 j/cm 2 laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre-treatment value after 14 days. Pemetrexed treatment followed by nPe6-PDt resulted in an 80% reduction in the tumor size and inhibited re-growth. nPe6-PDt followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re-growth. nPe6-PDt induced the expression of thymidylate synthase (tS), which confers resistance to pemetrexed, and nPe6-PDt followed by pemetrexed treatment did not enhance the treatment outcome in vivo. in conclusion, combination treatment, consisting of pemetrexed followed by nPe6-PDt, should be further investigated as a new treatment modality for MPM. in the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM.

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Section: Discussionsupporting

confidence: 48%

Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells

Maehara

Usuda

Ishizumi

et al. 2014

International Journal of Oncology

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“…We measured the amount of PpIX using fluorescence intensity analysis instead of direct PpIX measurement, thinking the former might have advantages in fluorescence quantification over other detection methods 10,16,23 Our results of the association between CDH13 expression and amount of intracellular PpIX in cell lines and tumor specimens strongly suggested that the CDH13 might act on PpIX accumulation. Results clearly demonstrated that CDH13 siRNA caused an increase of PpIX accumulation and 5-ALA-induced fluorescence in glioma cells, suggesting that CDH13 downregulation can improve the accuracy of PpIX fluorescence-guided discrimination of malignant cells.…”

Section: Discussionmentioning

confidence: 96%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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Object Gliomas contain aggressive malignant cancer, and resection rate remains an important factor in treatment. Currently, fluorescence-guided resection using orally administered 5-aminolevulinic acid (5-ALA) has proved to be beneficial in improving the prognosis of patients with gliomas. 5-ALA is metabolized to protoporphyrin IX (PpIX) that accumulates selectively in the tumor and exhibits strong fluorescence upon excitation, but glioma cells do not always respond to 5-ALA, which can result in incomplete or excessive resection. Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. To clarify the probable mechanisms underlying the variable induction of fluorescence and to improve fluorescence-guided surgery, the authors searched for key negative regulators of fluorescent signal induced by 5-ALA. Methods A comprehensive gene expression analysis was performed using microarrays in 11 pairs of tumor specimens, fluorescence-positive and fluorescence-negative tumors, and screened genes overexpressed specifically in fluorescence-negative tumors as the possible candidates for key negative regulators of 5-ALA–induced fluorescence. The most possible candidate was selected through annotation analysis in combination with a comparison of expression levels, and the relevance of expression of the selected gene to 5-ALA–induced fluorescence in tumor tissues was confirmed in the quantified expression levels. The biological significance of an identified gene in PpIX accumulation and 5-ALA–induced fluorescence was evaluated by in vitro PpIX fluorescence intensity analysis and in vitro PpIX fluorescence molecular imaging in 4 human glioblastoma cell lines (A1207, NMCG1, U251, and U373). Knockdown analyses using a specific small interfering RNA in U251 cells was also performed to determine the mechanisms of action and genes working as partners in the 5-ALA metabolic pathway. Results The authors chose 251 probes that showed remarkably high expression only in fluorescent-negative tumors (median intensity of expression signal > 1.0), and eventually the cadherin 13 gene (CDH13) was selected as the most possible determinant of 5-ALA–induced fluorescent signal in gliomas. The mean expression level of CDH13 in the fluorescence-negative gliomas was statistically higher than that in positive ones (p = 0.027), and knockdown of CDH13 expression enhanced the fluorescence image and increased the amount of PpIX 13-fold over controls (p < 0.001) in U251 glioma cells treated with 5-ALA. Comprehensive gene expression analysis of the CDH13-knockdown U251 cells demonstrated another two genes possibly involved in the PpIX biosynthesis: ATP-binding cassette transporter (ABCG2) significantly decreased in the CDH13 knockdown, while oligopeptide transporter 1 (PEPT1) increased. Conclusions The cadherin 13 gene might play a role in the PpIX accumulation pathway and act as a negative regulator of 5-ALA–induced fluorescence in glioma cells. Although further studies to clarify the mechanisms of action in the 5-ALA metabolic pathway would be indispensable, the results of this study might lead to a novel fluorescent marker able to overcome the obstacles of existing fluorescence-guided resection and improve the limited resection rate.

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“…It has been reported that the induction of differentiation enhanced PpIX accumulation in some cell lines, such as prostate cancer cells (51), fibroblasts, B16 cells (42) and keratinocytes (52). However, the relationship between tumour cell differentiation and photosensitizer accumulation is poorly defined (53) since some differentiation agents, such as butyrate, did not enhance PpIX accumulation whereas others, such as hexamethylene bisacetamide (HMBA) and methotrexate, did (43,54). To the best of our knowledge, this is the first evidence that a member of the coumarin group enhanced PpIX accumulation at least in melanoma cells; this observation was not reproduced in SW620 cells suggesting a cell-type specific effect.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle arrest and differentiation induction by 5,7-dimethoxycoumarin in melanoma cell lines

Alesiani

Cicconi²,

Mattei³

et al. 2008

Int J Oncol

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Abstract. In the present study we investigated the antiproliferative activity of 5,7-dimethoxycoumarin on the murine B16 and human A375 melanoma cell lines. The inhibitory concentration 50 (IC 50 ) was estimated for each cell line by preliminary assay of tetrazolium salt reduction (MTT). With Trypan blue exclusion test we detected a cytostatic but not cytotoxic effect of the treatment in melanoma cells: 5,7-dimethoxycoumarin significantly reduced cell proliferation in a time-and dose-dependent manner, blocking the cell cycle in the G 0 /G 1 phase both in B16 and A375 cells. Melanoma growth reduction was coupled to a differentiation process detected by monitoring some specific markers: i) morphological changes with development of dendrite-like projections from the cell surface; ii) melanin synthesis; and iii) PpIX accumulation. Induction of the differentiation process was more significant in murine melanoma cells, where the treatment irreversibly reduced cell growth. Consistent with G 0 /G 1 arrest and melanogenesis in B16 cells, 5,7-dimethoxycoumarin strongly decreased activation of the mitogen-activated protein kinase extracellular signal-related kinase 1/2, which is upregulated in many types of cancer. These findings suggest that 5,7-dimethoxycoumarin should be further investigated through studies both in vitro, to identify the binding partners for this compound, and in preclinical animal models.

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Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

Cited by 104 publications

References 35 publications

Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells

Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Cell cycle arrest and differentiation induction by 5,7-dimethoxycoumarin in melanoma cell lines

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