*2.1.9. Gastric cancer*

In gastric cancer, ATO and ABT-737, a small-molecule drug that inhibits Bcl-2/Bcl-xL antiapoptotic molecules, cooperatively suppressed the proliferation of human gastric cancer cell lines SGC7901 and MGC-803 [47]. Although ABT-737 has low solubility and oral bioavailability, the other Bcl-2 inhibitor ABT-199 has been developed for clinical use for the treatment of hematological malignancies including chronic lymphoid leukemia (CLL) [48].

#### *2.1.10. Urothelial carcinoma (UC)*

In urothelial carcinoma, Kuo et al. reported that 2-methoxyestradiol (2-ME), an endogenous derivative of 17β-estradiol, elicits synergistic cytotoxicity of human UC cell lines NTUB1 and T24 in combination with ATO, with a CI < 1.0 [49].

#### *2.1.11. Pancreatic cancer*

In pancreatic cancer, Wang et al. reported that parthenolide (PTL), a sesquiterpene lactone from the medical herb feverfew, enhances apoptosis of human pancreatic cancer cell lines PANC-1 and BxPC-3 by mediating ROS generation and subsequent caspase activation via the mitochondrial pathway [50]. The combined ATO-PTL treatment significantly reduced tumor growth rates of PANC-1 xenografts compared with those treated with either PTL or ATO alone [50]. Another report focused on the limited efficacy of ATO on cytotoxicity in pancreatic ductal adenocarcinoma probably because of the high-cellular ROS scavenging activity. Lang et al. reported that PX-478, a hypoxia-inducible factor-1 inhibitor, robustly strengthens the antigrowth and proapoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro by mediating ROS accumulation [51].

#### *2.1.12. Glioma and glioblastoma (GBM)*

In glioma, several reports indicated the effectiveness of arsenic for combination therapy. Kim et al. reported that ATO specifically increases expression of death receptor 5 (DR5), a death receptor of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a subset of human glioma cell lines but not in astrocytes [52]. They also showed that combined ATO and TRAIL treatment synergistically reduces the survival of glioma cells, with a CI < 1.0 [52]. ATO-radiation combination treatment enhanced autophagic effects in U118-MG cells through increased mitotic arrest and regulation of PI3K/Akt and ERK1/2 signaling pathways [53]. Similar observations were reported in human fibrosarcoma and osteosarcoma, where the combined treatment arrested their cell cycle at the G2 /M phase [54, 55]. ATO is a ROS inducer, and heme oxygenase-1 (HO-1) is known to be increased in arsenic-treated cells [56]. Liu et al. reported that HO-1 inhibition or Nrf2 knockdown significantly potentiated ATO-induced cytotoxic effects on glioma cells [57]. This result suggests that ATO-induced gene expression including the Nrf2 signaling pathway may be partly involved in the resistance of cancer cells to ATO. Dizaji et al. reported that combined treatment with ATO and silibinin, a natural polyphenolic flavonoid, synergistically induces apoptosis and inhibits invasiveness in the human GBM cell line U87MG, in which the expression of cathepsin B, uPA, MMP-2, MMP-9, membrane type 1-MMP, survivin, Bcl-2, and CA9 decreased after treatment [58]. Gülden et al. reported that combined treatment with ATO and silibinin reduces the viability of A-172 by mediating intracellular arsenic accumulation [59]. As described in lung cancer, BSO depleted cellular glutathione and acted synergistically with ATO in rat C6 astroglioma cells [60]. Karsy et al. investigated the effect of ATO and ATRA on neurosphere formation of U87MG possessing wild-type (wt) p53 and/ or codon-specific p53 mutant (R273H) [61]. They found that ATO and ATRA treatment could induce apoptosis of both U87-p53 (wt) and U87-p53 (R273H) and could potently suppress CSC properties in vitro [61]. It is well known that c-Myc is also required for the maintenance of CSCs of various cancers including GBM [62]. Yoshimura et al. showed that ATO and c-Myc inhibitor 10058-F4 coordinately enhanced differentiation of GBM CSCs and regressed GBM CSC tumor growth in vivo [63]. Primon et al. reported the involvement of cathepsin L (CatL) in the ATOinduced apoptotic effect [64, 65]. They found that knockdown of CatL enhances ATO-mediated in vitro cytotoxicity and apoptosis in both the GBM cell line U87MG [58] and pilocytic astrocytoma cell line MPA58 [65].
