*2.1.5. Cervical cancer*

Radiotherapy has been generally used for the treatment of patients with cervical cancer, which is the most common cancer among females worldwide, as a monotherapy and combined therapy with chemotherapeutics, such as platinum-based drugs. The combined ATO-radiation treatment was expectably reported to exert a beneficial antitumoral effect on cervical cancer cells in vitro and/or in vivo [18, 19]. Wei et al. reported that ATO decreases radiation-accelerated lung metastases probably via suppression of radiation-induced MMP-9 expression [18]. Kang et al. reported that ATO enhances the translocation of Bax protein to mitochondria and the phosphorylation level of Bcl-2, which were accompanied by activation of MAPKs including p38 and JNK [19]. Since NAC clearly inhibits the ATO-mediated cell killing as well as MAPK activation, ROS generation may play an important role in ATO-radiation-induced apoptosis. In addition to ATO, tetraarsenic oxide (TAO, As<sup>4</sup> O6 ) was shown to potentially exert an anticancer effect on cervical cancer cells. Kim et al. reported that the combined TAO and radachlorin/photodynamic therapy cooperatively suppress the proliferation of mouse TC-1 cells both in vitro and in vivo, where tumor suppressor p53 and the inducible p21 protein increased especially in combined treated tumor cells [20]. TAO was also reported to synergistically suppress tumor growth of human cervical carcinoma cell line CaSki when it was combined with CDDP [21]. The combined TAO-CDDP therapy dramatically increased the number of apoptotic cells, as similarly observed in other types of cancer cells when ATO was combined with CDDP [12, 15].

#### *2.1.6. Breast cancer*

Breast cancer is one of the leading causes of cancer-related deaths among women worldwide. In breast cancer cells, ATO was reported to reduce the expression of DNA methyltransferase-1 (DNMT1) and to induce the expression of estrogen receptor α (ERα), whose expression has been epidemiologically recognized to increase disease-free survival and indicate an overall better prognosis (**Figure 1B**) [22]. Subsequently, combined ATO and antiestrogen tamoxifen (TAM) therapy coordinately suppressed tumor growth of a human breast cancer cell line MDA-MB-435S both in vitro and in vivo [22]. ATO was reported to enhance 89Sr radiation treatment-induced apoptosis by partly modulating the Bcl-2/Bax ratio [23]. Guilbert et al. reported that ATO suppresses rapamycin (specific mTOR inhibitor)-induced phosphorylation of both ERK and Akt (Ser473), which leads to enhancement of the anticancer effect of rapamycin in vivo [24]. Cotylenin A (CN-A), a plant growth regulator, was reported to exert a favorable antitumor effect on breast cancer cells when it was co-incubated with ATO in vitro [25]. The combined CN-A-ATO treatment decreased survivin expression and increased caspase-7 expression by partly mediating ROS generation [25]. It has been reported that melatonin, a known natural antioxidant, enhances ATO-induced apoptosis by mediating ROS generation-induced MAPK activation including p38 and JNK in human breast cancer cell lines MDA-MB-231 and SK-BR-3 [26]. They also showed that mTOR inhibitor rapamycin further enhances the ATO-melatonin-induced apoptosis [26]. In addition to inorganic arsenite ATO, its intermediate metabolites monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII) exert more cytotoxicity toward breast cancer cells than ATO, implicating application of the arsenite-related intermediates in anticancer therapy for breast cancer [27]. The combined intermediates MMAIII and DMAIII cryptotanshinone (a natural quinoid diterpene isolated from *Salvia miltiorrhiza* roots) strongly induce apoptosis by mediating endoplasmic reticulum (ER) stress and/or ROS generation in MCF-7 cells [27].
