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Enhanced Antitumor Effect of Combined Triptolide and Ionizing Radiation

Authors' Affiliations: ¹ Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York; ² Department of Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China; and ³ Pancreas Surgery Center, Union Hospital of Tongji Medical College, Wuhan, Hubei, China

Requests for reprints: Paul Okunieff, Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642-8647. Phone: 585-275-2985; Fax: 585-275-1531; E-mail: Paul_Okunieff{at}URMC.Rochester.edu.

Purpose: The lack of effective treatment for pancreatic cancer results in a very low survival rate. This study explores the enhancement of the therapeutic effect on human pancreatic cancer via the combination of triptolide and ionizing radiation (IR).

Experimental Design: In vitro AsPC-1 human pancreatic cancer cells were treated with triptolide alone, IR alone, or triptolide plus IR. Cell proliferation was analyzed with sulforhodamine B (SRB) method and clonogenic survival; comparison of apoptosis induced by the above treatment was analyzed by annexin V–propidium iodide (PI) staining. Furthermore, the expression of apoptotic pathway intermediates was measured by the assay of caspase activity and Western blot. Mitochondrial transmembrane potential was determined by JC-1 assay. In vivo, AsPC-1 xenografts were treated with 0.25 mg/kg triptolide, 10 Gy IR, or triptolide plus IR. The tumors were measured for volume and weight at the end of the experiment. Tumor tissues were tested for terminal nucleotidyl transferase–mediated nick end labeling (TUNEL) and immunohistochemistry.

Results: The combination of triptolide plus IR reduced cell survival to 21% and enhanced apoptosis, compared with single treatment. In vivo, tumor growth of AsPC-1 xenografts was reduced further in the group treated with triptolide plus IR compared with single treatment. TUNEL and immunohistochemistry of caspase-3 cleavage in tumor tissues indicated that the combination of triptolide plus IR resulted in significantly enhanced apoptosis compared with single treatments.

Conclusions: Triptolide in combination with ionizing radiation produced synergistic antitumor effects on pancreatic cancer both in vitro and in vivo and seems promising in the combined modality therapy of pancreatic cancer.