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Modulation of cellular chemoresistance in keratinocytes by activation of different oncogenes
Author(s) -
SanchezPrieto Ricardo,
Vargas Juan Antonio,
Carnero Amancio,
Marchetti Elena,
Romero Jesus,
Durantez Alberto,
Lacal Juan Carlos,
Cajal Santiago Ramon Y
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910600218
Subject(s) - staurosporine , oncogene , cancer research , cisplatin , cytotoxicity , cytotoxic t cell , flow cytometry , protein kinase c , doxorubicin , cell culture , biology , microbiology and biotechnology , apoptosis , chemistry , pharmacology , cell cycle , kinase , in vitro , chemotherapy , biochemistry , genetics
Response to chemotherapeutic agents in malignant tumors depends on many factors, most of which are as yet unknown. We investigated the correlation between the activation of different oncogenes and protein‐kinase‐C(PKC) modulation, and the cytotoxicity of some of the most widely used anti‐cancer drugs. We transformed the murine keratinocyte cell line PAM 212, with different oncogenes (v‐H‐ ras , v‐ myc and adenovirus El a) and a mutant p53 suppressor gene ( mp53 ). The cytotoxic effect of cisplatin (CDDP), doxorubicin(DOX) and vincristine (VCR), together with the concomitant action of modulators of PKC, TPA and staurosporine were evaluated by the crystal‐violet method, thymidine incorporation and flow cytometry. We report that (a) the oncogene v‐H‐ ras induces resistance to CDDP (> 50%), DOX (> 25%) and VCR (> 20%); (b) the E l a oncogene induces only resistance to VCR (>40%) and marked sensitivity to CDDP and DOX; (c) the mp53 oncogene induces more resistance to VCR and insignificant resistance to the other drugs; and (d) activation of PKC by TPA increases the resistance to VCR and DOX in cells transformed by the v‐H‐ ras , while it significantly increases the lethality with CDDP of the E l a ‐transformed cells. Staurosporine increases the cytoxicity of all the drugs, especially in the E l a ‐transformed keratinocytes. In the flow‐cytometry analysis, the percentage of BUdR incorporation was related to sensitivity to anti‐cancer drugs. © 1995 Wiley‐Liss, Inc.