*2.1.13. Other combinations*

reported that buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, enhances ATOinduced apoptosis in A549 cells, in which the apoptosis was related to the increased level of intracellular ROS (**Figure 1A**) [43]. In addition, combined ATO-CDDP treatment induced apoptosis and synergistically suppressed the proliferation of human NSCLC cell lines A549 and H460, with CI values 0.5 and 0.6, respectively, where CI <1 defines synergism [44]. Lam et al. indicated that combined treatment with ATO and a selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 cooperatively suppresses tumor proliferation both in vitro and in vivo in the lung squamous cell carcinoma (SCC) cell line SK-MES-1, in which ATO-PD173074 decreased FGFR1, Akt, Src, c-Raf, and Erk, at least in part by mediating proteasomal degradation [45]. Gu et al. reported that ROS-mediated ER stress and mitochondrial dysfunction were

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

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

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

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].

involved in the apoptosis induced by resveratrol and ATO in A549 cells [46].

hematological malignancies including chronic lymphoid leukemia (CLL) [48].

*2.1.9. Gastric cancer*

*2.1.10. Urothelial carcinoma (UC)*

by mediating ROS accumulation [51].

*2.1.12. Glioma and glioblastoma (GBM)*

*2.1.11. Pancreatic cancer*

T24 in combination with ATO, with a CI < 1.0 [49].

40 Current Understanding of Apoptosis - Programmed Cell Death

Baumgartner et al. reported that ATO-mediated apoptosis is markedly enhanced by using the polyunsaturated fatty acid docosahexaenoic acid (DHA) in 12 different ATO-resistant solid tumor cell lines including breast, ovarian, colon, prostate, cervical, and pancreatic cancer, while there was no cytotoxicity in normal skin fibroblasts, human microvascular endothelial cells, and peripheral blood mononuclear cells derived from healthy donors [66]. Lin et al. reported that combined ATRA and ATO treatment synergistically inhibits the proliferation and induces apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro [67]. Kryeziu et al. found that combined treatment with ATO and erlotinib, a selective EGFR inhibitor, acts synergistically through accumulation of DNA damage by inhibiting EGFR-mediated DNA double-strand break repair in mesothelioma, HCC, colorectal carcinoma, osteosarcoma, thyroid carcinoma, and cervix carcinoma in vitro [68].
