Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines

Herman, Shoshy; Zurgil, Naomi; Deutsch, Mordechai

doi:10.1007/s00011-005-1355-8

Cited by 152 publications

(93 citation statements)

References 59 publications

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“…MTX is believed to induce apoptosis through oxidative stress that results in damage to DNA. 25 Supporting this hypothesis, apricot diet which contains polyphenols and flavonoids significantly decreased MTX-induced apoptosis in the rat. 24 Also, Vardi et al 27 indicated that bcarotene exhibited a protective effect on MTX-induced apoptosis in testicular cells..…”

Section: 22mentioning

confidence: 91%

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Protective effect of propolis on methotrexate-induced kidney injury in the rat

2016

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Objectives Propolis is a potent antioxidant and a free radical scavenger. Pharmacological induction of heat shock proteins (HSPs) has been investigated for restoring normal cellular function following an injury. In this study, effect of propolis on HSP-70 expression in methotrexate-induced nephrotoxicity and direct preventive effect of propolis in this toxicity were investigated. Material and methods A total of 40 male Wistar albino rats were divided into four groups: Group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20 mg/kg. Groups 3 and 4 received 100 mg/kg/day propolis (by oral gavage) for 15 d by the first day of the experimental protocol. Then the rats were decapitated under ketamine esthesia and their kidney tissues were removed. HSP-70 expression, apoptosis, and histopathological damage scores were then compared. Results MTX caused epithelial desquamation into the lumen of the tubules, dilatation, and congestion of the peritubular vessels and renal corpuscles with obscure Bowman's space. The number of apoptotic cells (p ¼ 0.000) and HSP-70 (p ¼ 0.002) expression were increased in group 2. Propolis prevented the rise in number of apoptotic cells (p ¼ 0.017), HSP-70 (p ¼ 0.000) expression, and improved kidney morphology. Conclusions It was found that methotrexate gives rise to serious damage in the kidney and propolis is a potent antioxidant agent in preventing kidney injury. ARTICLE HISTORY

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Section: 22mentioning

confidence: 91%

“…Similarly, in a study in rat kidney, authors showed increased apoptosis after MTX treatment. 24 Herman et al 25 and Mazur et al 26 showed that MTX causes apoptosis in T lymphocytes, human uterine cervix cancer, and the normal fibroblastic rat kidney. MTX is believed to induce apoptosis through oxidative stress that results in damage to DNA.…”

Section: 22mentioning

confidence: 99%

Protective effect of propolis on methotrexate-induced kidney injury in the rat

2016

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“…In addition, CAV1 was also induced in responders to anti-TNF agents (fold change 1.23), suggesting that a balance between pro-and antiapoptotic genes may contribute to MTX response. Indeed, MTX reduces cell viability, and this effect may be correlated with the induction of apoptosis, especially in synovial cells, T cells, and monocytes from patients with RA 29,30 ; these effects should be expected in MTX responders. In addition to apoptosis, MTX may also suppress T cell activation, mediated in part by adenosine 31 .…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression Profiles May Differentiate Responder and Nonresponder Patients with Rheumatoid Arthritis for Methotrexate (MTX) Monotherapy and MTX plus Tumor Necrosis Factor Inhibitor Combined Therapy

Oliveira

Fontana²,

Junta³

et al. 2012

J Rheumatol

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ABSTRACT. Objective. We aimed to evaluate whether the differential gene expression profiles of patients with rheumatoid arthritis (RA) could distinguish responders from nonresponders to methotrexate (MTX) and, in the case of MTX nonresponders, responsiveness to MTX plus anti-tumor necrosis factor-α (anti-TNF) combined therapy. Methods. We evaluated 25 patients with RA taking MTX 15-20 mg/week as a monotherapy (8 responders and 17 nonresponders). All MTX nonresponders received infliximab and were reassessed after 20 weeks to evaluate their anti-TNF responsiveness using the European League Against Rheumatism response criteria. A differential gene expression analysis from peripheral blood mononuclear cells was performed in terms of hierarchical gene clustering, and an evaluation of differentially expressed genes was performed using the significance analysis of microarrays program.Results. Hierarchical gene expression clustering discriminated MTX responders from nonresponders, and MTX plus anti-TNF responders from nonresponders. The evaluation of only highly modulated genes (fold change > 1.3 or < 0.7) yielded 5 induced (4 antiapoptotic and CCL4) and 4 repressed (4 proapoptotic) genes in MTX nonresponders compared to responders. In MTX plus anti-TNF nonresponders, the CCL4, CD83, and BCL2A1 genes were induced in relation to responders. Conclusion. Study of the gene expression profiles of RA peripheral blood cells permitted differentiation of responders from nonresponders to MTX and anti-TNF. Several candidate genes in MTX non-responders (CCL4, HTRA2, PRKCD, BCL2A1, CAV1, TNIP1, CASP8AP2, MXD1, and BTG2) and 3 genes in MTX plus anti-TNF nonresponders (CCL4, CD83, and BCL2A1) were identified for further

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“…Both methotrexate and raltitrexed endocytose the ligand-FAR complex, initially at the level of the CM, the CM FAR, and upon CM FAR endocytosis followed by intra-cellular disassociation, re-associate/bind to the sub-cellular membrane FARs, the MM FAR and the rough endoplasmic reticulum (RER) FAR inducing their endocytosis. This cumulates in increased sub-cellular vesiculization-mediated generation of pro-oxidant reactive oxygen species (109,110), and in case of the mitochondria, vesiculization-mediated loss of MM electromotive potential (109,(111)(112)(113). Therefore, the mechanism for anti-folate chemoxenobiotic-mediated cellular cytotoxicity is FAR endocytosis-driven sub-cellular pro-oxidant oxidative stress (114)(115)(116)(117), particularly mitochondrial, whereby there is only limited potential for CM receptor endocytosis-mediated (Pseudo) 3ary indirect pressuromodulation (110,118) (Table VIII and Fig.…”

Section: Small Molecule Xenobiotics That Cause Dual Carboxylation-facmentioning

confidence: 99%

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Sarin¹

2015

Molecular and Clinical Oncology

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Abstract. For proper determination of the apoptotic potential of chemoxenobiotics in synergism, it is important to understand the modes, levels and character of interactions of chemoxenobiotics with cells in the context of predicted conserved biophysical properties. Chemoxenobiotic structures are studied with respect to atom distribution over molecular space, the predicted overall octanol-to-water partition coefficient (Log OWPC; unitless) and molecular size viz a viz van der Waals diameter (vdWD). The Log OWPC-to-vdWD (nm -1 ) parameter is determined, and where applicable, hydrophilic interacting moiety/core-to-vdWD (nm -1 ) and lipophilic incorporating hydrophobic moiety/core-to-vdWD (nm -1 ) parameters of their part-structures are determined. The cellular and sub-cellular level interactions of the spectrum of xenobiotic chemotherapies have been characterized, for which a classification system has been developed based on predicted conserved biophysical properties with respect to the mode of chemotherapeutic effect. The findings of this study are applicable towards improving the effectiveness of existing combination chemotherapy regimens and the predictive accuracy of personalized cancer treatment algorithms as well as towards the selection of appropriate novel xenobiotics with the potential to be potent chemotherapeutics for dendrimer nanoparticle-based effective transvascular delivery. IntroductionSmall molecules non-endogenous to the biological system, often referred to as xenobiotics, include a diverse variety of molecules, simple organic toxicants with uncomplicated structures and natural eukaryotic antibiotics and synthetic molecules of more complicated structures and cytotoxic properties (1), the latter of which have chemotherapeutic properties. Although small molecule chemoxenobiotics, of various traditional classes, form the basis of present synergistic cancer treatment strategies, their clinical efficacy remains questionable for the treatment of solid and hematopoietic malignancies alike, upon surgical resection in the former, and during bone marrow irradiation-transplantation and after in the latter. For this reason, a better understanding of the modes and character underlying molecular cellular interactions is necessary, particularly for the purposes of improving the tumor tissue selectiveness of enhanced permeation and retention (EPR)-based chemotherapy (2), which has a prolonged blood half-life but is non-selective for solid tumor foci. Along these lines, there has been relatively recent translational advancement towards the development of optimally sized dendrimer nanoparticle-based small molecule chemotherapy at ~9 nm (H D ) (3-7), which selectively delivers small molecule chemoxenobiotics into solid malignancies at effective concentrations without systemic toxicity (4,8). As such, with optimally sized dendrimer nanoparticle-based small molecule chemotherapy, there is the potential for complete tumor regression (3,9) in lieu of the possibility for the development of drug resistance phenotypes (1...

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Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines

Cited by 152 publications

References 59 publications

Protective effect of propolis on methotrexate-induced kidney injury in the rat

Protective effect of propolis on methotrexate-induced kidney injury in the rat

Differential Gene Expression Profiles May Differentiate Responder and Nonresponder Patients with Rheumatoid Arthritis for Methotrexate (MTX) Monotherapy and MTX plus Tumor Necrosis Factor Inhibitor Combined Therapy

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

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