Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells

Abstract

We have previously reported that arsenic trioxide (ATO) could inhibit glioma growth both in vitro and in vivo, and demonstrated its potent therapeutic effects on gliomas. In this study we showed that ATO induced cell damage and heme oxygenase-1 (HO-1) expression in glioma cells via ROS generation. HO-1 inducer clearly protected from ATO-induced cell death and ROS generation, and HO-1 inhibitor led to a significant increase in cell death and ROS generation induced by ATO. In addition, knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) strongly inhibited HO-1 expression induced by ATO, and significantly enhanced ATO-induced oxidative damage. Our results demonstrated, for the first time, that HO-1 inhibition or Nrf2 knockdown significantly potentiated ATO's effects on glioma cells. Considering that HO-1 is highly expressed in glioma tissues, administration of ATO in combination with either HO-1 inhibitor or Nrf2 knockdown may act as a new approach to the treatment of glioma.

Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways

“…Hormetic effect of arsenic-induced HO-1 expression HO-1 has been shown to protect cells in different stress models, but the results of studies regarding the cytoprotective effect of HO-1 up-regulation in response to arsenic have been inconclusive (Liu et al 2011b;Morales et al 2009). As a result, we used zinc protoporphyrin IX (ZnPP), a well-documented HO-1 competitive inhibitor, to examine the effect of HO-1 on arsenic-induced cytotoxicity.…”

An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses

“…A number of studies have shown that an increase in ROS-scavenging and -detoxifying enzymes protects cells, whereas blocking these defense systems confers sensitivity to ionizing radiation (IR) or chemotherapeutic drugs [6][7][8]. Most of these antioxidant proteins are regulated through the interaction of the transcription factor Nrf2 (NF-E2-related factor 2) with a cis-element in an antioxidant-response element (ARE) sequence located in the promoter of the corresponding gene.…”

Antioxidant Adaptive Response of Malignant Glioma Related to Resistance to Antitumor Treatment

“…We found that knockdown of HO-1 by means of small interfering RNA (siRNA) resulted in the induction of apoptosis in SW480 human colon cancer cells in culture [Fang et al, 2003]. Liu et al [2011] reported that Nrf2 knockdown effectively led to suppressed HO-1 expression and enhanced sensitization to arsenic trioxide-induced apoptosis in cultured human glioma cells U251MG and A172. Quite recently, HO-1 expression was found to be regulated post-transcriptionally by microRNA (miRNA).…”

“…Antitumor and chemosensitizing effects of metalloporphyrin-type HO inhibitors such as zinc protoporphyrin (ZnPP) and cobalt protoporphyrin have been demonstrated in cultured tumor cells and in animal models [Doi et al, 1999;Fang et al, 2003Fang et al, , 2004bLiu et al, 2011;Tanaka et al, 2003]. Combining chemotherapeutic agents such as camptothecin, doxorubicin, arsenic trioxide, gemcitabine, and imatinib, as well as irradiation, with ZnPP or related inhibitors may lead to improved antitumor treatment [Fang et al, 2004b;Gleixner et al, 2009;Liu et al, 2011;Mayerhofer et al, 2008;Miyake et al, 2010].…”

“…Combining chemotherapeutic agents such as camptothecin, doxorubicin, arsenic trioxide, gemcitabine, and imatinib, as well as irradiation, with ZnPP or related inhibitors may lead to improved antitumor treatment [Fang et al, 2004b;Gleixner et al, 2009;Liu et al, 2011;Mayerhofer et al, 2008;Miyake et al, 2010].…”