Effect of arsenic trioxide on multidrug resistant hepatocellular carcinoma cells
Introduction
The effect of arsenic trioxide (As2O3) on cancer treatment is widely studied after the discovery of its anti-tumor effect by a group of Chinese doctors in 1970s [1]. In fact, the first use of As2O3 in cancer therapy was to treat acute promyelocytic leukemia (APL). The results of both the in vitro and clinical trials showed that As2O3 is effective in inhibiting the growth of APL [2], [3]. Recent studies showed that As2O3 is also effective in inhibiting the growth of non-APL cancer cells like myeloid leukemia [4], gastric cancers [5], neuroblastoma [6], esophageal carcinoma [7], head and neck cancers [8], as well as breast cancer [9], [10]. Our previous study and other studies showed that As2O3 is effective in inhibiting the in vitro growth of human hepatocellular carcinoma HepG2 cells and human breast tumor MCF-7 cells via induction of apoptosis [9], [10], [11], [12], [13]. In vivo studies also showed the effects on tumor bearing mice and rat model [14], [15]. In the present study, we further studied the effect of As2O3 on multidrug resistant cancers. The multidrug resistant human hepatocellular carcinoma cell line, R-HepG2, was used. It is developed by our group and is characterized with overexpression of mdr1 gene and P-glycoprotein [16]. The effectiveness of As2O3 on R-HepG2 cells as well as the action mechanism of As2O3 on R-HepG2 cells were studied. Moreover, As2O3 was tested for its possibility to act as a substrate of P-glycoprotein.
Section snippets
Chemicals
As2O3 was purchased from Sigma Chemical Company and it was prepared as a stock of 10 mM in phosphate buffered saline and kept at 4 °C.
Cell cultures
Human hepatocellular carcinoma cell line, HepG2, was purchased from American Type Culture Collection. It was cultured with RPMI medium supplemented with 10% fetal bovine serum and maintained at 37 °C in a humidified atmosphere of 5% carbon dioxide/95% air. Multidrug resistant human hepatocellular carcinoma cell line, R-HepG2, was developed by our group [16]. To
Effect of doxorubicin on cell proliferation of the parental HepG2 Cells and R-HepG2 cells
Doxorubicin is one of the commonest anti-cancer drugs and it is effective in inhibiting the growth of a wide variety of cancers like lung, breast, liver and bladder cancers. Our study also showed that doxorubicin was effective in inhibiting the cell proliferation of HepG2 cells in a dose- and time-dependent manner (Fig. 1(A)). Although, the IC50 of doxorubicin on HepG2 cells was greater than 20 μM upon 1-day treatment, it dropped significantly upon further incubation. The IC50 of Doxorubicin for
Discussion
Multidrug resistant cancer cells may develop in patients upon prolonged treatment with anti-cancer drugs. The appearance of multidrug resistance poses great obstacle in the chemotherapy of cancer because higher dosage of drugs are needed to be administered to the patients which will cause severe adverse effects to the hosts [17]. Our previous study showed that As2O3 is effective in inhibiting the growth of human hepatocellular carcinoma, HepG2 cells via induction of apoptosis [11]. This finding
Acknowledgements
This study was supported by a direct grant and an earmarked grant (CUHK 4399/03M) from Research Grants Council, Hong Kong.
References (21)
- et al.
Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients
Blood
(1999) - et al.
Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARα independent manner
Blood
(1998) - et al.
Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro
Biochem. Biophys. Res. Commun.
(2000) - et al.
Effect of arsenic trioxide on cell cycle arrest in head and neck cancer cell line PCl-1
Biochem. Biophys. Res. Commun.
(1999) - et al.
Effect of arsenic trioxide on human hepatocellular carcinoma HepG2 cells: inhibition of proliferation and induction of apoptosis
Life Sci.
(2002) - et al.
Inhibition by arsenic trioxide of human hepatoma cell growth
Cancer Lett.
(2002) - et al.
Inhibition of P-glycoprotein expression and reversal of drug resistance of human hepatoma HepG2 cells by multidrug resistance gene (mdr1) antisense RNA
Life Sci.
(2000) - et al.
Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukaemia (APL): II Clinical efficacy and pharmacokinetics in relapsed patients
Blood
(1997) Ancient remedy performs new tricks
Science
(1996)- et al.
Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide
New Engl. J. Med.
(1998)
Cited by (27)
Distinct toxicological characteristics and mechanisms of Hg<sup>2+</sup> and MeHg in Tetrahymena under low concentration exposure
2017, Aquatic ToxicologyCitation Excerpt :To ensure the viability of Tetrahymena cells and for the convenience when centrifuging, the organisms were cultured in 1.5 mL tubes (Axygen, Corning, USA). Tetrahymena were exposed at the early stage of logarithmic phase for 24 h. Briefly, cell membrane status was examined by detecting the increase in red fluorescence after propidium iodide (PI for short, BD Biosciences, San Jose, CA, USA) staining described in previous research (Chan et al., 2006). Dichlorofluorescein diacetate (DCF-DA, Sigma, USA) was added in the cell solutions and the final concentration was 10 μM.
Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: An in vitro and in vivo study
2017, Food and Chemical ToxicologyCitation Excerpt :Cancer cells have increased ROS accumulation and antioxidant defense system when compared to their normal counterparts to adapt to oxidative stress-facilitated cell proliferation (Behrend et al., 2003) and chemo-resistance (Pervaiz and Mv, 2015). Mounting evidences suggest that, many ROS promoting drugs showed potential anticancer activity, either by increasing oxidative stress (Motexafin gadolinium and β-Lapachone (ARQ 501)) (Magda and Millera, 2006; Bey et al., 2007)) or, by inhibiting the antioxidant defense system (Buthionine sulphoximine, Imexon, Phenylethyl isothiocyanate and 2-methoxyestradiol) (Dvorakova et al., 2000; Kito et al., 2002; Trachootham et al., 2006; Ehteda et al., 2013), in many cancers including hepatocellular carcinoma (Siu et al., 2002; Wang et al., 2003; Chan et al., 2006). Black pepper, “the king of spices” added flavor to folk medicine for ages by treating conditions ranging from epilepsy to abdominal disorders (Ahmad et al., 2012).
The inhibition of constitutive androstane receptor-mediated pathway enhances the effects of anticancer agents in ovarian cancer cells
2014, Biochemical PharmacologyCitation Excerpt :In addition, we investigated whether the anticancer drug effect of CITCO could invert the influence of anticancer drugs (Fig. 1). As for As2O3, it has been shown to be effective in treating multidrug resistance in human hepatocellular carcinoma cells overexpressing P-glycoprotein and acute myeloid leukemia disease, oral squamous carcinoma, prostate and ovarian cancer [22–25,38]. As2O3 exerts its effect via induction of apoptosis.
Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells
2010, Environmental Toxicology and PharmacologyCitation Excerpt :We first investigated the effect of As3+ on cellular metabolic activity by MTT assay. The selected dose of 50 μM As3+ had no apparent effect on HepG2 cell viability either at 8 h or 24 h post-exposure (Figs. 1A and 2A), which is in agreement with previous reports where a minimal toxicity was observed at the selected dose and a clear As3+ time–dose-dependent toxicity is demonstrated by the MTT metabolic assay (Chan et al., 2006; Lin et al., 2005b; Tchounwou et al., 2003). The effect of 50 μM As3+ on the vital cellular antioxidant GSH of HepG2 cells was also studied in our work.
Dithiothreitol abrogates the effect of arsenic trioxide on normal rat liver mitochondria and human hepatocellular carcinoma cells
2008, Toxicology and Applied Pharmacology