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Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells
Author(s) -
Schnelldorfer Thomas,
Gansauge Susanne,
Gansauge Frank,
Schlosser Sophia,
Beger Hans G.,
Nussler Andreas K.
Publication year - 2000
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20001001)89:7<1440::aid-cncr5>3.0.co;2-0
Subject(s) - glutathione , apoptosis , medicine , pancreatic cancer , cancer , cancer research , cancer cell , cell growth , programmed cell death , microbiology and biotechnology , biochemistry , biology , enzyme
BACKGROUND Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC‐1, and the significance of GSH in tumor resistance to chemotherapy. METHODS Cell growth in AsPC‐1 was initiated through transforming growth factor‐alpha (TGF‐α) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy‐induced apoptosis was studied using 5‐fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens. RESULTS Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 ± 2.3 vs. 8.8 ± 1.4 nmol/mg protein; P < 0.004). Incubation of AsPC‐1 with TGF‐α or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH‐depleted cells with TGF‐α did not stimulate cell growth. In addition, GSH‐depletion resulted in an increased rate of apoptosis after melphalan (6.3 ± 0.3 % vs. 11.2 ± 0.3 %; P < 0.001), but not after 5‐fluorouracil treatment. CONCLUSIONS Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC‐1 cells. Therefore, GSH‐depletion may improve the effectivity of adjuvant therapy in pancreatic carcinoma. Cancer 2000;89:1440–7. © 2000 American Cancer Society.