Expression of p53 in cisplatin-resistant ovarian cancer cell lines: Modulation with the novel platinum analogue (1R, 2R- diaminocyclohexane)(trans-diacetato)(dichloro)platinum(IV)

George S. Hagopian, Gordon Mills, Abdul R. Khokhar, Robert C. Bast, Zahid H. Siddik

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

The compound (IR,2R- diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug- induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH- acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 μM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 μM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 μM) than it was in mutant or null models (IC50, 2.7-11.3 μM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH- acetato-Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild- type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild- type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH- acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (≤25 μM) of DACH-acetato-Pt induced marked increases in p53 and p21(Waf1/Cip1) expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21(Waf1/Cip1) until the drug concentration was increased to 125 μM. In HPV 16 E6 transfectants of OVCA- 429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21(Waf1/Cip1) were abrogated. This suggests that p21(Waf1/Cip1) increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.

Original languageEnglish (US)
Pages (from-to)655-663
Number of pages9
JournalClinical Cancer Research
Volume5
Issue number3
StatePublished - Mar 1 1999
Externally publishedYes

Fingerprint

Platinum
Ovarian Neoplasms
Cisplatin
Cell Line
Inhibitory Concentration 50
Human papillomavirus 16
Cell Cycle
Pharmaceutical Preparations
(diaminocyclohexane)(diacetato)(dichloro)platinum
Null Lymphocytes
Aptitude
Tumor Suppressor Genes
Antineoplastic Agents
Substance-Related Disorders
Neoplasms
Plasmids
Clone Cells
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Expression of p53 in cisplatin-resistant ovarian cancer cell lines : Modulation with the novel platinum analogue (1R, 2R- diaminocyclohexane)(trans-diacetato)(dichloro)platinum(IV). / Hagopian, George S.; Mills, Gordon; Khokhar, Abdul R.; Bast, Robert C.; Siddik, Zahid H.

In: Clinical Cancer Research, Vol. 5, No. 3, 01.03.1999, p. 655-663.

Research output: Contribution to journalArticle

@article{a5fce8cdf80747769863af1088bcc962,
title = "Expression of p53 in cisplatin-resistant ovarian cancer cell lines: Modulation with the novel platinum analogue (1R, 2R- diaminocyclohexane)(trans-diacetato)(dichloro)platinum(IV)",
abstract = "The compound (IR,2R- diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug- induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH- acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 μM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 μM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 μM) than it was in mutant or null models (IC50, 2.7-11.3 μM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH- acetato-Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild- type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild- type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH- acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (≤25 μM) of DACH-acetato-Pt induced marked increases in p53 and p21(Waf1/Cip1) expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21(Waf1/Cip1) until the drug concentration was increased to 125 μM. In HPV 16 E6 transfectants of OVCA- 429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21(Waf1/Cip1) were abrogated. This suggests that p21(Waf1/Cip1) increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.",
author = "Hagopian, {George S.} and Gordon Mills and Khokhar, {Abdul R.} and Bast, {Robert C.} and Siddik, {Zahid H.}",
year = "1999",
month = "3",
day = "1",
language = "English (US)",
volume = "5",
pages = "655--663",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Expression of p53 in cisplatin-resistant ovarian cancer cell lines

T2 - Modulation with the novel platinum analogue (1R, 2R- diaminocyclohexane)(trans-diacetato)(dichloro)platinum(IV)

AU - Hagopian, George S.

AU - Mills, Gordon

AU - Khokhar, Abdul R.

AU - Bast, Robert C.

AU - Siddik, Zahid H.

PY - 1999/3/1

Y1 - 1999/3/1

N2 - The compound (IR,2R- diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug- induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH- acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 μM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 μM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 μM) than it was in mutant or null models (IC50, 2.7-11.3 μM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH- acetato-Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild- type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild- type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH- acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (≤25 μM) of DACH-acetato-Pt induced marked increases in p53 and p21(Waf1/Cip1) expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21(Waf1/Cip1) until the drug concentration was increased to 125 μM. In HPV 16 E6 transfectants of OVCA- 429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21(Waf1/Cip1) were abrogated. This suggests that p21(Waf1/Cip1) increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.

AB - The compound (IR,2R- diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug- induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH- acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 μM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 μM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 μM) than it was in mutant or null models (IC50, 2.7-11.3 μM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH- acetato-Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild- type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild- type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH- acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (≤25 μM) of DACH-acetato-Pt induced marked increases in p53 and p21(Waf1/Cip1) expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21(Waf1/Cip1) until the drug concentration was increased to 125 μM. In HPV 16 E6 transfectants of OVCA- 429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21(Waf1/Cip1) were abrogated. This suggests that p21(Waf1/Cip1) increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.

UR - http://www.scopus.com/inward/record.url?scp=0033037410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033037410&partnerID=8YFLogxK

M3 - Article

C2 - 10100719

AN - SCOPUS:0033037410

VL - 5

SP - 655

EP - 663

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -