Enhanced antitumor effect of combined gemcitabine and proton radiation in the treatment of pancreatic cancer.
OBJECTIVE
This study evaluates the efficacy of combining proton irradiation with gemcitabine, and the role the inhibitor of apoptosis proteins survivin and X-linked inhibitor of apoptosis protein (XIAP) play in the radiosensitive versus radioresistant status of pancreatic cancer.


METHODS
The radioresistant (PANC-1) and radiosensitive (MIA PaCa-2) pancreatic carcinoma cells' response to combined gemcitabine and proton irradiation was compared. Cells were treated with 0.1 to 500 microM gemcitabine and 0- to 15-Gy proton irradiation after which trypan blue and flow cytometry were used to determine changes in the cell cycle and apoptosis. Expression levels of survivin and XIAP were measured using Western blotting. Combination therapy with gemcitabine for 24 hours followed by 10-Gy proton irradiation proved most effective.


RESULTS
Gemcitabine and proton irradiation resulted in increased survivin levels with little apoptosis. However, combination therapy resulted in robust apoptotic induction with a concomitant survivin and XIAP reduction in the MIA PaCa-2 cells with little effect in the PANC-1 cells. Small interfering RNA studies confirmed a role for XIAP in the radioresistance of PANC-1 cells.


CONCLUSIONS
Our data demonstrate that combining gemcitabine and proton irradiation enhances apoptosis in human pancreatic cancer cells when XIAP levels decrease. Therefore, XIAP may play an important role in human pancreatic cancer proton radioresistance.
Galloway
Nicholas R
NR
Department of Basic Sciences, Center for Health Disparities Research and Molecular Medicine, Loma Linda University, CA, 92350, USA.
Aspe
Jonathan R
JR
Sellers
Chelsey
C
Wall
Nathan R
NR
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D000077022:Survivin; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine