Tetraarsenic oxide and cisplatin induce apoptotic synergism in cervical cancer

Tetraarsenic oxide (As4O6, TAO) is a new arsenic compound that inhibits cell growth and induces apoptosis in human cervical cancer cell lines. In the present study, we report that the growth of tumor cells (CaSki) was inhibited by treatment with TAO alone or in combination with cisplatin or paclitaxel in vitro and in vivo. Proliferation was assessed by WST-1 assay, and apoptosis was assessed by Annexin-V/PI FACS analysis in the CaSki cell line treated with a single agent or with the combinations of two agents. Expression of apoptosis-related proteins was analyzed by western blot analysis. A mouse xenograft model using CaSki cells was used to determine the in vivo activity of tetraarsenic oxide alone and in combination with cisplatin or paclitaxel by estimation of tumor size. At the end of the experiment, tumor tissue from each mouse was removed and processed for TUNEL analysis for confirmation of apoptotic cells. TAO was able to inhibit cell proliferation in a time- and dose-dependent manner. A combination of TAO and cisplatin effectively induced apoptosis by activating caspase-3. Using a mouse xenograft model, the sizes of tumors which were treated with a single agent and with a combination of agents decreased in a time-dependent manner. A combination of TAO and cisplatin resulted in a significantly reduced tumor size (P<0.05). The data for the histochemical staining of TUNEL-positive cells showed that the number of apoptotic cells was significantly increased by the combination of TAO and cisplatin. Thus, TAO is a good candidate for use in a combined regimen with cisplatin for patients with cervical cancer.