Abstract 9: Efficacy and functional study of tetraarsenic oxide as an anticancer drug in cervical cancer cell lines and cervical cancer patient-derived xenograft mouse
Authors: Lee Jeong-Won , Hwang Jae Ryoung , Cho Young-Jae , Kim Ji-Hye , Ryu Ji Yoon , Baik E-Sun 
Published: August 2018

Background: Arsenic compound has been used as a medicine in China and has been studied to treat acute promyelocytic leukemia, hepatocellular carcinoma, and melanoma. Tetraarsenic oxide (TAO; As4O6) is an inorganic arsenic compound that has been demonstrated to inhibit angiogenesis and cell growth in cervical cancer cells. In this study, we demonstrated anti-cancer effect of TAO in cervical cancer patient-derived xenograft (PDX) mouse model and the functional mechanism related with cervical cancer cell death.

Materials & Methods: We used SiHa, Caski, and HeLa cells for cervical cancer cells and HUVEC cells to study functional mechanism of TAO in an in vitro. MTT assay was performed to assess cell death and MMP-2-specific ELISA assay was used to detect MMP-2 expression. To establish the patient-derived xenograft (PDX) mouse model of cervical cancer, surgical patient tumor specimens were reduced to small pieces (less than 2-3 mm), implanted into the subrenal capsules of the left kidneys of BALB/C nude mice, and propagated by serial transplantation. The PDX model used in this study was generated with a tumor that was histologically defined as a FIGO stage Ib1 invasive squamous cell carcinoma. The patient was a 46-year-old woman who received primary debulking surgery followed by radiation therapy for 28 times.

Results: We measured IC50 of TAO in cervical cancer and HUVEC cells. IC50 of TAO in SiHa, Caski, and HUVEC was around 3 uM and it was about 0.6 uM in HeLa cells. Although TAO inhibited MMP-2 expression, an important protein for angiogenesis, in both cervical cancer cell lines and HUVEC cells, the functional mechanism was different in between cervical cancer cells and HUVEC cells. TAO inhibited Akt activation in SiHa, Caski, and HeLa. However, TAO had no effect on activation of Akt in HUVEC cells. TAO inhibited expression of VEGF receptor 2 in HUVEC cells but not in cervical cancer cells. We found that TAO inhibited autophagy determined by p62 expression level in cervical cancer cells but not in HUVEC cells. Cervical cancer PDX mouse study demonstrated that TAO inhibited tumor growth.

Conclusions: TAO inhibited cell growth of cervical cancer cells and HUVEC. The functional signaling pathway of TAO-induced cell death might different in between cervical cancer cells and endothelial cell, HUVEC. TAO inhibited tumor growth in cervical cancer PDX mouse probably through inhibition of cancer cell growth and inhibition of angiogenesis via inhibition of endothelial cell growth. These results suggest that TAO may be considered as a novel therapeutic compound for the treatment of cervical cancer.

Citation Format: Jeong-Won Lee, Jae Ryoung Hwang, Young-Jae Cho, Ji-Hye Kim, Ji Yoon Ryu, E-Sun Baik. Efficacy and functional study of tetraarsenic oxide as an anticancer drug in cervical cancer cell lines and cervical cancer patient-derived xenograft mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 9.