Synthesis, In Vitro Anticancer Evaluation, and Interference with Cell Cycle Progression of N‐Phosphoamino Acid Esters of Zidovudine and Stavudine

Wu, Yao‐Wen; Xiao, Qiang; Jiang, Yuyang; Fu, Hua; Ju, Yi‐Hsu; Zhao, Yufen

doi:10.1081/ncn-200034057

Cited by 13 publications

(10 citation statements)

References 27 publications

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“…Cell cycle abnormalities induced by AZT have been previously observed in human HL60 (Roskrow & Wickramasinghe, 1990), Jurkat (Wu et al, 2004), Hela (Olivero et al, 2005) and lymphoblastoid cells (Olivero et al, 2010). Our results showed that the combination of AZT and emodin caused an accumulation of K562/ADM cells in S phase, which is consistent with Oliver's findings (Olivero et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell cycle arrest and suppressing MDR1 mRNA/p-gp protein expression

Chen¹,

Liu²,

Sun³

et al. 2013

Pharmaceutical Biology

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Context: Previous studies have demonstrated that both 3 0 -azido-3 0 -deoxythymidine (AZT) and emodin, a traditional chemotherapy agent, can inhibit the growth of many types of cancer cells. Objective: This study aimed to evaluate the effect of AZT and emodin on adriamycin-resistant human chronic myelogenous leukemia (K562/ADM) cells, determine the expression of multidrug resistance 1 (MDR1) mRNA/p-glycoprotein (p-gp) protein, a protein known to induce resistance to anticancer agents, and to elucidate the underlying molecular mechanisms. Materials and methods: K562/ADM cells were treated with AZT (10-160 mM) or emodin (5-80 mM) for 24, 48 and 72 h and cell viability was measured using the MTT assay. The effect of AZT (16.5, 33 and 66 mM) and emodin (6.1, 17.6 and 33.2 mM) on K562/ADM cell cycle distribution was determined by flow cytometry, and MDR1 mRNA/p-gp protein expression was determined by real time RT-PCR and western blotting. Results: The growth suppression of emodin was dramatically enhanced by AZT in K562/ADM cells. The IC 50 of AZT and emodin was lower than that of emodin alone. All examined combinations of AZT and emodin yielded a synergetic effect (CI51). Furthermore, AZT and emodin altered the cell cycle distribution and led to an accumulation of cells in S phase. Meanwhile, the expression of MDR1 mRNA/p-gp protein was markedly decreased. Discussion and conclusion: These results show a synergistic growth-inhibitory effect of AZT and emodin in K562/ADM cells, which is achieved through S phase arrest. MDR1 might ultimately be responsible for these phenomena.

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Section: Discussionsupporting

confidence: 92%

AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell cycle arrest and suppressing MDR1 mRNA/p-gp protein expression

Chen¹,

Liu²,

Sun³

et al. 2013

Pharmaceutical Biology

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“…The resulting damaged DNA might either delay cell cycle progression until the damage is repaired or cause apoptotic cell death (Melana et al 1998; Falchetti et al 2005; Humer et al 2008; Fang and Beland 2009; Fang et al 2009b). In addition, recent studies have demonstrated that XPC, via the nucleotide excision repair pathway, is essential for the repair of AZT-induced DNA damage in human HepG2 cells and THLE2 cells (Wu et al 2011, 2013) In the current study, molecular and cellular function pathway analysis indicated that most of the 253 common genes altered in the same direction by AZT at the equi-toxic concentrations in both HepG2 cells and THLE2 cells were involved in cell death and survival, cellular growth and proliferation, cell cycle, and DNA replication, recombination, and repair (Table 2), which is in consistent with previous studies (Fang and Beland 2009; Collier et al 2003; Wu et al 2004; Melana et al 1998; Roskrow and Wickramasinghe 1990; Falchetti et al 2005; Humer et al 2008). …”

Section: Discussionsupporting

confidence: 91%

“…The differential sensitivity of cancer cells to AZT has been related to a combination of effects, including a delay of cell cycle progression, the induction of apoptosis, and a decrease in telomerase activity (Melana et al 1998; Collier et al 2003; Wu et al 2004; Falchetti et al 2005; Humer et al 2008; Fang and Beland 2009). Cancer cells also have higher growth rates than normal cells, with a concomitant higher rate of thymidine turnover, which could contribute to their increased sensitivity to AZT (Melana et al 1998; Humer et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine

Fang

Han

et al. 2013

Arch Toxicol

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Zidovudine (3′-azido-3′-deoxythymidine; AZT) is the most widely used nucleoside reverse transcriptase inhibitor for the treatment of AIDS patients and prevention of mother-to-child transmission of HIV-1. Previously, we demonstrated that AZT had significantly greater growth inhibitory effects upon the human liver carcinoma cell line HepG2 as compared to the immortalized human liver cell line THLE2. We have now used gene expression profiling to determine the molecular pathways associated with toxicity in both cell lines. HepG2 cells were incubated with 0, 2, 20, or 100 μM AZT for 2 weeks; THLE2 cells were treated with 0, 50, 500, or 2,500 μM AZT, concentrations that 2013 were equi-toxic to those used in the HepG2 cells. After the treatment, total RNA was isolated and subjected to microarray analysis. Global analysis of gene expression, with a false discovery rate ≤0.01 and a fold change ≥1.5, indicated that 6- to 70-fold more genes were differentially expressed in a significant concentration-dependent manner in HepG2 cells when compared to THLE2 cells. Comparative analysis indicated that 7 % of these genes were common to both cell lines. Among the common differentially expressed genes, 70 % changed in the same direction, most of which were associated with cell death and survival, cell cycle, cell growth and proliferation, and DNA replication, recombination, and repair. As determined by the uptake of [methyl-3H]AZT, the intracellular levels of total AZT were approximately twofold higher in THLE2 cells than in HepG2 cells. The expression of thymidine kinase 1 (TK1) and UDP-glucuronosyltransferase 2B7 (UGT2B7) genes that regulate the metabolic activation and deactivation of AZT, respectively, was increased in HepG2 cells but decreased in THLE2 cells after treatment with AZT. This differential response in AZT metabolism was confirmed by real-time PCR, western blotting, and/or enzymatic assays. These data indicate that molecular pathways involved with cell death and survival, cell cycle, cell growth and proliferation, and DNA replication, recombination, and repair are involved in the toxicities associated with AZT in both human cell lines, and that the difference in expression of TK1 and UGT2B7 in response to AZT treatment in HepG2 cells and THLE2 cells might explain why HepG2 cells are more sensitive than THLE2 cells to the toxicity of AZT.

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“…Cell cycle abnormalities induced by AZT have been previously reported in human HeLa (Olivero et al , 2005), HL60 (Roskrow and Wickramasinghe, 1990), and Jurkat cells (Wu et al , 2004). Prior studies performed in our laboratory, using HeLa cells, revealed a delay in the cell cycle, with a dose-related significant increase in percentage of S-phase cell accumulation after 24 h of exposure to 63–500μM AZT.…”

Section: Discussionmentioning

confidence: 87%

Long-term AZT Exposure Alters the Metabolic Capacity of Cultured Human Lymphoblastoid Cells

Olivero

Vazquez

Cooch

et al. 2010

Toxicological Sciences

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The antiretroviral efficacy of 3′-azido-3′-deoxythymidine (AZT) is dependent upon intracellular mono-, di-, and triphosphorylation and incorporation into DNA in place of thymidine. Thymidine kinase 1 (TK-1) catalyzes the first step of this pathway. MOLT-3, human lymphoblastoid cells, were exposed to AZT continuously for 14 passages (P1–P14) and cultured for an additional 14 passages (P15–P28) without AZT. Progressive and irreversible depletion of the enzymatically active form of the TK-1 24-kDa monomer with loss of active protein was demonstrated during P1–P5 of AZT exposure. From P15 to P28, both the 24- and the 48-kDa forms of TK-1 were undetectable and a tetrameric 96-kDa form was present. AZT-DNA incorporation was observed with values of 150, 133, and 108 molecules of AZT/106 nucleotides at the 10μM plasma-equivalent AZT dose at P1, P5, and P14, respectively. An exposure-related increase in the frequency of micronuclei (MN) was observed in cells exposed to either 10 or 800μM AZT during P1–P14. Analysis of the cell cycle profile revealed an accumulation of S-phase cells and a decrease in G1-phase cells during exposure to 800μM AZT for 14 passages. When MOLT-3 cells were grown in AZT-free media (P15–P29), there was a reduction in AZT-DNA incorporation and MN formation; however, TK-1 depletion and the persistence of S-phase delay were unchanged. These data suggest that in addition to known mutagenic mechanisms, cells may become resistant to AZT partially through inactivation of TK-1 and through modulation of cell cycle components.

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Synthesis, In Vitro Anticancer Evaluation, and Interference with Cell Cycle Progression of N‐Phosphoamino Acid Esters of Zidovudine and Stavudine

Cited by 13 publications

References 27 publications

AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell cycle arrest and suppressing MDR1 mRNA/p-gp protein expression

AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell cycle arrest and suppressing MDR1 mRNA/p-gp protein expression

Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine

Long-term AZT Exposure Alters the Metabolic Capacity of Cultured Human Lymphoblastoid Cells

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