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

Abstract

Arsenic trioxide (As(2)O(3)) has been established to be an effective agent for treating acute promyleocytic leukemia. Laboratory data suggest that As(2)O(3) induces apoptosis of several solid tumor cells including lung cancer cells. 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 studied the cytotoxic effect of As(2)O(3) on human lung adenocarcinoma cell lines A549 and A549/R (resistant to vincristine, adriamycin and mitomycin etc.) grown under normoxic and hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 5, 10 and 15 microM As(2)O(3) induced evident growth inhibition and apoptosis in A549 cells as well as A549/R cells after 48 hours of exposure. In contrast, the conventional chemotherapeutic drug vincristine showed lowered efficiency in hypoxic A549 cells. As(2)O(3) induced G(2)/M cell cycle arrest in both normoxic and hypoxic A549 cells. As(2)O(3) significantly decreased the messenger RNA (mRNA) levels of Cyclin B(1) and survivin and the protein levels of Cyclin B(1), phospho-CDC(2) (Thr 161) and survivin in both normoxic and hypoxic A549 cells. Together, our findings indicated that As(2)O(3) significantly inhibited the proliferation of lung cancer cells via G(2)/M cell cycle arrest and induction of apoptosis at both normoxia and hypoxia, and the induction of apoptosis was associated with down regulation of survivin.

Arsenic Trioxide Induces Apoptosis via Specific Signaling Pathways in HT- 29 Colon Cancer Cells

“…Arsenic trioxide has been shown to act on cells by influencing cell cycle arrest [ 61 , 62 ]. In the current study, we investigated the apoptotic effects of ATO in vitro on the human colon cancer cells by cell cycle distribution and apoptosis by flow cytometry.…”

Arsenic trioxide (As2O3) induces apoptosis and necrosis mediated cell death through mitochondrial membrane potential damage and elevated production of reactive oxygen species in PLHC-1 fish cell line

“…Similar results of necrosis, not apoptosis, following the G2/M arrest in colorectal cancer cells treated with aspirin (Subbegowda and Frommel, 1998). As 2 O 3 has been reported to induce cell cycle arrest in mammalian cell lines at both G1 (Zhang et al ., 1998) and G2/M phases (Qu et al, 2009), depending on the cell line used. Wang et al(2004) report on two fish cell lines (JF and TO-2) exposed to arsenic, which underwent arrest in two different phases-subG1 for JF cells and G2/M arrest for TO-2 cells, which suggests that fish cell lines are also variable in their cell cycle response to As 2 O 3.…”

Disruption of Mitotic Progression by Arsenic

“…Indeed, Trisenox®, the pharmacological formulation of ATO used in the clinic to treat APL, is prepared by dissolution of ATO in 30 mM NaOH followed by titration with HCl to near neutral pH (http://www.trisenox.com/hcp/trisenoxprescribing-information.pdf). ATO and sodium arsenite induce apoptosis in vitro in many types of cancer cells derived from solid tumors including melanoma [25], lung cancer [26], neuroblastoma [27], ovarian cancer [28,29], transitional cell carcinoma [30], and prostate cancer [29]. Arsenite has long been known to disrupt mitosis, but normal diploid cells can survive this disruption albeit with an increase in aneuploidy.…”