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Inadequately irradiated primary tumor of primary Lewis lung carcinoma (LLC-LM) in vivo is a mechanism of radiation-enhanced LLC-LM cells in pulmonary metastasis. We observed a CXCL1/GRO alpha, is a member of the CXC family of chemokines is elevated after radiation therapy. CXCL1 protein is function with to bind the G-protein coupled receptor chemokine (C-X-C motif) receptor 2 (CXCR2) to recruit neutrophils. Reparixin is an inhibitor of CXCR2, and demonstrates activity against malignant behavior of human cancer cells xenografts. The effect of Reparixin on the radiotherapy of LLC-LM primary tumor and the effects on distant metastases have not been studied. The right thighs of C57BL/6 mice (n = 40) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of four groups: no irradiation, 10 Gy in one fraction, Reparixin (0.1mg/kg/day, for 5days) plus 10 Gy in one fraction, or Reparixin( 0.1mg/kg/day, for 5days) only . Tumors were clinically irradiated in each treatment group. All of the mice were killed within 21 days after the completion of radiation therapy. Examination of their lungs revealed >13 (range, 13-22) surface metastases in the 10 Gy treated mice with 3 (range, 2-7) in the no irradiation mice, in Reparixin plus 10 Gy treated mice with 6(range, 4-13), in Reparixin treated mice with 2 (range, 2-6). The lung weights had increased from 0.22 g (range, 0.21-0.24 g) in the no irradiation mice to 0.43 g (range 0.37-0.61) in the 10 Gy treated mice, in Reparixin plus 10 Gy treated mice with 0.31(range, 0.26-0.41), in Reparixin treated mice with 0.23 (range, 0.2-0.25 g). In the surface metastases and lung weight, Reparixin plus irradiation treatment were statistically significant with P < 0.001 when compare with irradiation alone. Other hand, the tumor growth curve also demonstrated that the Reparixin enhanced the tumor control of irradiation of LLC-LM tumor. In this model, the use of inadequately radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining CXCR2 inhibitor with radiation therapy may enhance local tumor control and reduce distant metastases. Citation Format: Chia-lun Chang, Yi-Hsin Liang, Szu-yuan Wu. CXCR2 inhibitor Reparixin enhances local tumor control and reduces distant metastases in mouse tumor radiotherapy [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 LB-313.

Prostate cancer is a leading cause of cancer death in men in developed countries. Radiotherapy is the main treatment to prostate cancer. Dose escalation of irradiation with image guide rasdiotherapy and intensity modulated radiotherapy were used with more and more evidences in prostate cancer patients and bring in longer PSA-free survival time. Although the evolution of radiation techniques bring better outcomes, but modern modalities were not avaliable in non-western world. Radiation enhancement is still an improtant issus in prostate cancer in non-western world, especially in androgen independnt prostate cancer. The epidermal growth factor receptor (EGFR) network has rich targets for prostate cancer killing. The chimeric monoclonal antibody Cetuximab (IMC-A12, Erbitux®) binds to EGFR and prevents its intracellular signaling. Currently, it is approved for treatment of wild-type KRAS colon and head and neck cancer. The effect and mechanisms of Erbitux and radiotherapy are still not clear. In this study, we evaluated the effects of combining the EGFR inhibition and radiation on PC-3 prostate cancer cells. PC-3 cells were treated with various doses(1,2.5,5 and 10 ug/ml) of anti-EGFR antibody (CETUXIMAB) and irradiation(5, 7.5 Gy). The results revealed that 5 and 10 ug/ml of CETUXIMAB significnatly reduced the colony formation. The cell cycle analysis revealed that CETUXIMAB significnatly enhanced the radiation induced G2/M phase arrest and subG1 peak increasing. The Hoechst staining and DNA laddering analysis revealed radiation and CETUXIMAB combined use will induced more apoptotic bodies or DNA fragmentation than radiation alone use. By using a apaptosis protein array, we found that several apaptosis related protein (Catalase, cIAP-1, Clusterin, Fas, HIF-1α, HSP27, HSP60, HSP70, SMAC and Survivin) were significantly downregulated in radiation and CETUXIMAB combined group. Taken together, our results demonstrated that Erbitux enhanced apoptosis effects of radiation on PC-3. Citation Format: Chia-lun Chang, Szu-Yuan Wu. Cetixumab enhanced apoptosis effects of radiation on human prostate cancer cell line PC-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 825. doi:10.1158/1538-7445.AM2017-825

H460 is a non-small cell lung cancer (NSCLC) cell with multidrug resistance (MDR) against a variety of anti-cancer drugs such as cisplatin and transforming growth factor-beta (TGF-beta). It has been reported that hypoxia can trigger the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the subsequent production of P-glycoprotein (P-gp, the archetype of MDR associated proteins or MRPs) that eventually lead to chemotherapeutic resistance of various cancer cell lines as well as NSCLC patients. The primary concern of this study was to know would hypoxia promote drug resistance of H460 cells via MRPs (MRP1 and MRP3). The experimental strategies applied were to evaluate the hypoxic impacts upon: 1) the drug resistance of H460 cells against doxorubicin (DOX, a commonly used chemotherapeutic drug in many cancer treatments), using MTT assay; 2) the expression of MRP1, MRP3 and HIF-1alpha of H460 cells in the absence or presence of DOX, using Western blot analysis; 3) the intracellular accumulation of DOX in H460 cells, using flow cytometry. The current results showed that DOX triggered a dose- and time-dependent cell death of H460. A hypoxia-induced DOX resistance was observed in H460 cells. Western blot analysis further showed that DOX-decreased MRP1 was further exacerbated under hypoxic condition that precluded the possible involvement of MRP1 in hypoxia-induced drug resistance. DOX on contrary increased the expression of MRP3. The potential contribution of MRP3 to hypoxia-induced DOX resistance and its role in pumping out of DOX from H460 cells are currently investigated in our laboratory. Finally, hypoxia-induced HIF-1alpha remained still high in the presence of DOX, suggesting a potential role of HIF-1alpha in promoting the DOX resistance of H460. Results from the study can uncover the molecular mechanisms underneath hypoxia-induced DOX resistance of H460 that consequently can lead to therapeutic target(s) for treatment of NSCLC cells (H460). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2011-3803