Bone Marrow Chemoprotection without Compromise of Chemotherapy Efficacy in a Rat Brain Tumor Model

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178

Cisplatin (CDDP) is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo CDDP toxicities. For ototoxicity studies, CDDP (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. Auditory brainstem response thresholds at 4 to 20 kHz were tested before and 7 days post-treatment. STS (8 g/m 2 i.v.) was administered at 4, 8, or 12 h after CDDP. For nephrotoxicity studies, rats were treated with CDDP intraperitoneally (10 mg/kg) before or after NAC (400 mg/kg) or STS (8 g/m 2 ), and blood urea nitrogen (BUN) and creatinine concentrations were measured after 3 days. In vitro cytotoxicity and chemoprotection in human tumor cell lines were assessed by cell viability and immunoblotting assays. Rats treated with STS 4 h after CDDP exhibited no hearing change. The STS 8-h group had less otoprotection, whereas 12-h rats had ototoxicity. CDDP induced high BUN and creatinine, corresponding to renal tubule toxicities. All NAC-treated animals showed normal BUN and reduced creatinine levels compared with CDDP alone and no histopathological evidence of nephrotoxicity. Delayed STS treatment was not consistently protective against nephrotoxicity. STS administration fully protected against the in vitro cytotoxic and apoptotic effects of CDDP if added within 2 h of CDDP, but chemoprotection decreased if STS administration was 4 h, and was minimal by 6 h, after CDDP. Thus, the chemoprotection route and timing of administration can be manipulated to maintain CDDP antitumor efficacy while protecting against toxicities.

Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Protection against Cisplatin-Induced Toxicities byN-Acetylcysteine and Sodium Thiosulfate as Assessed at the Molecular, Cellular, and in Vivo Levels

Dickey

Muldoon³

et al. 2005

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“…In addition, enolate cytoprotection could stem the toxicity of drugs that are significant electrophiles, e.g., cisplatin, clopidogrel (Dedon and Borch, 1987;Singh et al, 2011). This suggestion is feasible, since electrophile-mediated toxicity can often be prevented without affecting the therapeutic (e.g., antineoplastic) efficacy of these drugs (Borch et al, 1980;Neuwelt et al, 2004). Finally, many environmental chemicals are electrophiles (e.g., acrolein, acrylamide, methylmercury) that produce toxicity as a consequence of acute or chronic exposure.…”

Section: Acetylcyclopentanone Prevents Acetaminophen Hepatotoxicitymentioning

confidence: 99%

Protective Properties of 2-Acetylcyclopentanone in a Mouse Model of Acetaminophen Hepatotoxicity

Zhang

Gavin

Geohagen

et al. 2013

Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile-or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80-2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40-7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80-2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-pbenzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants.

“…Our previous studies demonstrated that NAC protects against alkylating chemotherapy cytotoxicity in vitro , blocks ototoxicity in rats treated with cisplatin (Dickey et al, 2004), and reduces chemotherapy-induced bone marrow toxicity in rats . We have found that thiol chemoprotection can be obtained without blocking the antitumor effects of chemotherapy (Muldoon et al, 2000;Neuwelt et al, 2004). Nonetheless, chemoprotectants have had relatively limited clinical use due to concerns of impaired antitumor efficacy.…”

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confidence: 99%

The Chemoprotective Agent N-Acetylcysteine Blocks Cisplatin-Induced Apoptosis through Caspase Signaling Pathway

Muldoon

Neuwelt

2004

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172

105

Thiols such as N-acetylcysteine (NAC) are increasingly used in clinical trials of platinum chemotherapy as chemoprotectants. NAC can prevent cisdiamminedichloroplatinum (cisplatin)-induced ototoxicity, nephrotoxicity, and gastrointestinal toxicity; however, the molecular mechanisms of NAC on apoptosis and cisplatin cytotoxicity remain unknown. We investigated cisplatin cytotoxicity and NAC chemoprotection in human tumor cell lines, as assessed by immunoblotting and immunocytochemistry. Cisplatin cytotoxicity was associated with nuclear translocation of apoptosis induction factor, expression of the pro-apoptotic Bax protein, cleavage of caspases 3 and 9, and cleavage of PARP. NAC administration reversed the cytotoxic and apoptotic effects if added concurrent with cisplatin or up to 2 h after cisplatin, but chemoprotection was reduced if NAC administration was delayed more than 2 h and was minimal by 8 h after cisplatin. Expression of tumor suppressor p53 and the cell cycle regulatory protein p21 was stimulated within 5 to 10 min by cisplatin in p53-positive LX-1 small cell lung carcinoma cells, and this effect was blocked by NAC. In p53-negative SKOV3 cells, cisplatin toxicity and NAC chemoprotection remained effective, suggesting that chemoprotection may be mediated through both p53-dependent and -independent pathways. Specific kinase inhibitors demonstrated that cisplatin induced apoptosis through the p38 mitogen-activated protein kinase (MAPK) pathway, not the extracellular signal-regulated kinase MAPK pathway. These results show that NAC blocks both the death receptor and the mitochondrial apoptotic pathways induced by cisplatin. The time course for NAC chemoprotection after cisplatin matches our previous in vivo results and provides an opportunity to manipulate route and timing to maintain cisplatin antitumor efficacy while protecting against chemotherapy side effects.