Modification of cyclophosphamide-induced clastogenesis and apoptosis in rats by α-lipoic acid

Selvakumar, E.; Prahalathan, Chidambaram; Varalakshmi, P.; Kumarasamy, P.; Saravanan, R.

doi:10.1016/j.mrgentox.2006.03.005

Cited by 14 publications

(9 citation statements)

References 31 publications

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“…Treatment with ␣-LA improved the viability of bone marrow cells following irradiation, as observed after other cytotoxic chemotherapeutic treatments, e.g., cyclophosphamide (44). Injection of ␣-LA in vivo protects connective tissue in experimental models of arthritis (29) and inflammatory bone disease (13,19).…”

Section: Discussionmentioning

confidence: 84%

Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

Kondo

Yumoto

Alwood

et al. 2010

Journal of Applied Physiology

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Exposure of astronauts in space to radiation during weightlessness may contribute to subsequent bone loss. Gamma irradiation of postpubertal mice rapidly increases the number of bone-resorbing osteoclasts and causes bone loss in cancellous tissue; similar changes occur in skeletal diseases associated with oxidative stress. Therefore, we hypothesized that increased oxidative stress mediates radiation-induced bone loss and that musculoskeletal disuse changes the sensitivity of cancellous tissue to radiation exposure. Musculoskeletal disuse by hindlimb unloading (1 or 2 wk) or total body gamma irradiation (1 or 2 Gy of (137)Cs) of 4-mo-old, male C57BL/6 mice each decreased cancellous bone volume fraction in the proximal tibiae and lumbar vertebrae. The extent of radiation-induced acute cancellous bone loss in tibiae and lumbar vertebrae was similar in normally loaded and hindlimb-unloaded mice. Similarly, osteoclast surface in the tibiae increased 46% as a result of irradiation, 47% as a result of hindlimb unloading, and 64% as a result of irradiation + hindlimb unloading compared with normally loaded mice. Irradiation, but not hindlimb unloading, reduced viability and increased apoptosis of marrow cells and caused oxidative damage to lipids within mineralized tissue. Irradiation also stimulated generation of reactive oxygen species in marrow cells. Furthermore, injection of alpha-lipoic acid, an antioxidant, mitigated the acute bone loss caused by irradiation. Together, these results showed that disuse and gamma irradiation, alone or in combination, caused a similar degree of acute cancellous bone loss and shared a common cellular mechanism of increased bone resorption. Furthermore, irradiation, but not disuse, may increase the number of osteoclasts and the extent of acute bone loss via increased reactive oxygen species production and ensuing oxidative damage, implying different molecular mechanisms. The finding that alpha-lipoic acid protected cancellous tissue from the detrimental effects of irradiation has potential relevance to astronauts and radiotherapy patients.

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Section: Discussionmentioning

confidence: 84%

Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

Kondo

Yumoto

Alwood

et al. 2010

Journal of Applied Physiology

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“…However, CPA also possesses a wide toxicity to normal cells in human and experimental animals (Estlin et al, 2001; Chan and Yeung, 2006). CPA exerts cytotoxicity by inducing apoptotic gene expression changes in cellular signaling pathways (Yamashita et al, 2007; Mammon et al, 2006; Selvakumar et al, 2006a,b), causing cellular and chromosome damages (Mammon et al, 2006; Selvakumar et al, 2006a,b), resulting in abnormal changes in the activities of enzyme and levels of non‐enzymic antioxidants (Selvakumar et al, 2006a,b; Revnic et al, 2005; Lopez and Luderer, 2004; Medina et al, 2004). Moreover, it is worthy to point out there are reports that CPA‐induced neurotoxicity was potented by activate excitotoxic mechanisms in vitro and in vivo (Rzeski et al, 2004; Jansen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Developmental neurotoxicity role of cyclophosphamide on post‐neural tube closure of rodents in vitro and in vivo

Xiao

Zhao

et al. 2007

Intl J of Devlp Neuroscience

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To evaluate the possible developmental role of cyclophosphamide on post-neural tube closure of rodents, the 46 pregnant rats of 2.5-3 months old were randomly divided into five groups. On the 13th day of gestation, the rats in control and experimental groups were treated with physiological saline and cyclophosphamide (7.5, 10.5, 12.5 and 15.0 mg/kg bw), respectively. On the 14th day of gestation, three rats each selected randomly from control and experimental (12.5 mg/kg bw) group, respectively, were executed and the embryo brains were checked using both light microscope and transmission electron microscope. Neurocytotoxic effects of cyclophosphamide were determined using tetrazolium dye (MTT) assay, single cell gel electrophoresis, flow cytometry and scanning electron microscope. Compared with control group, the malformation incidence of the experimental groups (except the group 7.5 mg/kg bw) was significantly higher, especially in 12.5 mg/kg bw group (malformation incidence 98%, lethality 0). Neural tube serial section of fetus showed the apoptotic morphological features after 24 h cyclophosphamide administrated. Cyclophosphamide (8 microg/ml) decreased the growth and viability of neurons, damaged nuclear DNA and induced early apoptotic morphological changes. Our study shows that the teratogenesis of cyclophosphamide after neural tube closure are involved in cyclophosphamide-induced neuronal apoptosis and DNA damage.

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“…This damage, if not correctly repaired, can lead to genomic instability and increase the risk of developing cancer. DNA damages include single-strand breaks (SSBs), double-strand breaks (DSBs), alkaline labile sites and various species of oxidized purines and pyrimidines (Selvakumar et al 2006b;Shay et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Antigenotoxic effect of lipoic acid against mitomycin-C in human lymphocyte cultures

et al. 2012

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Antitumor agents are used in therapy against many forms of human cancer. One of these is mitomycin-C (MMC). As with many agents, it can interact with biological molecules and can induce genetic hazards in non-tumor cells. One of the possible approaches to protect DNA from this damage is to supply antioxidants that can remove free radicals produced by antitumor agents. Lipoic acid (LA) is known as one of the most powerful antioxidants. The aim of this study was to investigate antigenotoxic effects of LA against MMC induced chromosomal aberrations (CA), sister chromatid exchanges (SCE) and micronucleus (MN) formation in human lymphocytes. Lymphocytes were treated with 0.2 μg MMC/heparinized mL for 48 h. Three different concentrations (0.5, 1, 2 μg/mL) of LA were used together with MMC in three different applications; 1 h pre-treatment, simultaneous treatment and 1 h post-treatment. A negative, a positive and a solvent control were also included. In all the cultures treated with MMC + LA, the frequency of abnormal cells and CA/cell significantly decreased compared to MMC. Statistically significant reduction was also observed in SCE/cell and MN frequencies in all treatments. These results demonstrated anticlastogenic and antimutagenic effects of LA against MMC induced genotoxicity. LA showed the most efficient effect during 1 h pretreatment. On the other hand, MMC + LA treatments induced significant reduction in mitotic index than that of MMC treatment alone. These results are encouraging that LA can be a possible chemopreventive agent in tumorigenesis in both cancer patients and in health care persons handling anti-cancer drugs.

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Modification of cyclophosphamide-induced clastogenesis and apoptosis in rats by α-lipoic acid

Cited by 14 publications

References 31 publications

Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

Developmental neurotoxicity role of cyclophosphamide on post‐neural tube closure of rodents in vitro and in vivo

Antigenotoxic effect of lipoic acid against mitomycin-C in human lymphocyte cultures

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