Blockade of MGMT Expression by O-6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis

    Authors

    S. D. Konduri; J. Ticku; G. C. Bobustuc; R. M. Sutphin; J. Colon; B. Isley; K. K. Bhakat; S. S. Kalkunte;C. H. Baker

    Abbreviated Journal Title

    Clin. Cancer Res.

    Keywords

    HUMAN O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; CELL-CYCLE; ALKYLATING-AGENTS; DRUG-RESISTANCE; GENE-EXPRESSION; FACTOR RECEPTOR; POTENTIAL ROLE; P53; PROTEIN; THERAPY; Oncology

    Abstract

    Purpose: We sought to determine whether administration of a MGMT blocker, O-6-benzyl guanine (O(6)BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth. Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O(6)BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated. Results: O(6)BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O(6)BG. In sharp contrast, protein expression and mRNA message of p21(cip1) were significantly increased. Interestingly, O(6)BG increases p53-mediated p21(cip1) transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p2l promoter. Furthermore, an increase in p21(cip1) and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O(6)BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O(6)BG inhibited expression of MGMT and cyclins, and increased expression of P21(cip1). Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis. Conclusions: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O(6)BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. (Clin Cancer Res 2009;15(19):6087-95)

    Journal Title

    Clinical Cancer Research

    Volume

    15

    Issue/Number

    19

    Publication Date

    1-1-2009

    Document Type

    Article

    Language

    English

    First Page

    6087

    Last Page

    6095

    WOS Identifier

    WOS:000270498700020

    ISSN

    1078-0432

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