Multidrug-resistant neuroblastoma cells are responsive to arsenic trioxide at both normoxia and hypoxia

Abstract

Despite intensive treatment, the outcome of high-risk neuroblastoma patients is poor with acquired multidrug resistance as an important cause. Previously, our group has shown that arsenic trioxide (As 2 O 3 ) kills multidrugresistant neuroblastoma cells in vitro and in vivo at clinically tolerable doses. Regions of tissue hypoxia often arise in aggressive solid tumors, and hypoxic tumors exhibit augmented invasiveness and metastatic ability in several malignancies. Furthermore, hypoxia may impair the treatment efficiency; therefore, we have studied the cytotoxic effect of As 2 O 3 on neuroblastoma cells grown under normoxic as well as hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 2 and 4 Mmol/L As 2 O 3 induced evident cell death in the drug-sensitive SH-SY5Y and IMR-32 cells as well as in the multidrugresistant SK-N-BE(2)c (with a mutated p53) and SK-N-FI cells after 72 hours of exposure. In contrast, the conventional chemotherapeutic drug etoposide showed lowered efficiency in hypoxic IMR-32 cells. In accordance with our previously published results, although not to the same extent as in their normoxic counterparts, Bax is proteolytically cleaved also in neuroblastoma cells exposed to As 2 O 3 at hypoxia. This suggests that similar molecular mechanisms are involved in As 2 O 3 -induced neuroblastoma cell death during hypoxia compared with normoxia. Together, our results support As 2 O 3 as a potential candidate drug as a complement to conventional treatments for high-risk neuroblastoma patients and perhaps also for patients with other multidrug-resistant solid tumors. [Mol Cancer Ther 2005;4(7):1128 -35]

Arsenic trioxide and neuroblastoma cytotoxicity

“…Our findings that pancaspase inhibition does not block arsenic trioxide-induced cell death or Bax cleavage and that the fraction of cytoplasmic vs mitochondrial cytochrome c in arsenic trioxide-treated neuroblastoma cells is small, further support a non-mitochondrial p18 Bax dependent death route (Karlsson et al, 2004). We also show that in conformity with arsenic trioxide treatment in normoxia, proteolytic activation of the proapoptotic protein Bax takes place when hypoxic neuroblastoma cells are treated with arsenic trioxide (Karlsson et al, 2005). Bax cleavage is not as pronounced, however, and it is possible that other cell death mechanisms are activated as a complement under hypoxic conditions.…”

“…We therefore investigated whether a low oxygen level (1% O 2 ) results in deteriorated cytotoxic effects of arsenic trioxide in different neuroblastoma cells. Our data show that the cytotoxic effect is retained under hypoxic conditions, even in multidrug-resistant neuroblastoma cells such as SK-N-BE(2)c and SK-N-FI (Karlsson et al, 2005). Despite that the neuroblastoma cells subjected to hypoxia is dividing somewhat more slowly, the cytotoxic effect of arsenic trioxide is maintained.…”

“…Despite that the neuroblastoma cells subjected to hypoxia is dividing somewhat more slowly, the cytotoxic effect of arsenic trioxide is maintained. In contrast, the cell death induced by the conventionally used drug etoposide was significantly impaired in etoposidesensitive neuroblastoma cell lines cultivated at hypoxia (Karlsson et al, 2005). Since hypoxic areas are frequent in solid tumors, these results highlight arsenic trioxide as a potential drug in treatment of patients with relapsed neuroblastomas that have ceased to respond to established therapy.…”

Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells

“…At clinically tolerable concentrations, As 2 O 3 also induces cell death in multidrug-resistant neuroblastoma cells in vitro and in vivo (9,10). The cytotoxic effect of As 2 O 3 is retained in neuroblastoma cells at hypoxia (11), a property of potential clinical importance because hypoxic areas are frequent in solid tumors and have been linked to drug-resistant phenotypes (12).…”

Arsenic trioxide inhibits the growth of human lung cancer cell lines via cell cycle arrest and induction of apoptosis at both normoxia and hypoxia

“…It is therefore of great significance to investigate novel chemotherapeutic drugs that are effective to kill tumour cells at hypoxia. Some studies showed that the cytotoxic effect of arsenic trioxide (As 2 O 3 ) on malignant cells was not reduced at hypoxia (Kalsson et al, 2005;Yan et al, 2005). As 2 O 3 , a potent anticancer agent, has been used for decades by Chinese investigators to treat acute promyelocytic leukemia (APL) patients.…”