The epigenetics of ovarian cancer drug resistance and resensitization

doi:10.1016/j.ajog.2004.05.025

American Journal of Obstetrics and Gynecology

Volume 191, Issue 5, November 2004, Pages 1552-1572

https://doi.org/10.1016/j.ajog.2004.05.025 Get rights and content

Ovarian cancer is the most lethal of all gynecologic neoplasms. Early-stage malignancy is frequently asymptomatic and difficult to detect and thus, by the time of diagnosis, most women have advanced disease. Most of these patients, although initially responsive, eventually develop and succumb to drug-resistant metastases. The success of typical postsurgical regimens, usually a platinum/taxane combination, is limited by primary tumors being intrinsically refractory to treatment and initially responsive tumors becoming refractory to treatment, due to the emergence of drug-resistant tumor cells. This review highlights a prominent role for epigenetics, particularly aberrant DNA methylation and histone acetylation, in both intrinsic and acquired drug-resistance genetic pathways in ovarian cancer. Administration of therapies that reverse epigenetic “silencing” of tumor suppressors and other genes involved in drug response cascades could prove useful in the management of drug-resistant ovarian cancer patients. In this review, we summarize recent advances in the use of methyltransferase and histone deacetylase inhibitors and possible synergistic combinations of these to achieve maximal tumor suppressor gene re-expression. Moreover, when used in combination with conventional chemotherapeutic agents, epigenetic-based therapies may provide a means to resensitize ovarian tumors to the proven cytotoxic activities of conventional chemotherapeutics.

Section snippets

DNA methylation

The term epigenetics refers to heritable DNA modifications that occur outside of primary base-coding sequences. The most common of these modifications is methylation of cytosines, usually located within the dinucleotide CpG.19., 20. This modification is catalyzed by enzymes known as DNA methyltransferases (DNMTs), of which three are known in humans: DNMT1, DNMT3a, and DNMT3b.²¹ DNMT1 is primarily involved in maintenance of methylation patterns, whereas DNMTs 3a and 3b effect de novo DNA

Epigenetic markers as prognostic indicators

DNA methylation profiling. As several aberrantly methylated loci have been identified in ovarian cancer, an emerging diagnostic strategy is to use such loci as prognostic and/or predictive markers. Prognostic markers refer to those associated with overall clinical outcome, whereas predictive markers are those used to monitor therapeutic response.⁷⁸ Distinguishing these two types of biomarkers is clinically quite difficult; however, examination of methylation alterations of specific genes during

Conclusions

Epigenetic alterations have been firmly demonstrated to play a role in tumor initiation, development, and progression. Aberrations in DNA methylation and histone deacetylation almost certainly also contribute to progression to a drug-resistant state. As these aberrations occur in several genes involved in apoptotic and differentiation pathways, their correction might allow for resensitization of tumor cells to drugs that affect such pathways. Figure 3 shows three hypothetical ovarian cancer

Acknowledgment

We thank Phil Abbosh and John Montgomery for constructive review of this manuscript.

References (258)

J.S. Barnholtz-Sloan et al.
Ovarian cancer: changes in patterns at diagnosis and relative survival over the last three decades
Am J Obstet Gynecol
(2003)
P.J. DiSaia et al.
Treatment of ovarian cancer: new strategies
Gynecol Oncol
(2003)
D.G. Mutch
Surgical management of ovarian cancer
Semin Oncol
(2002)
G.C.E. Stuart
First-line treatment regimens and the role of consolidation therapy in advanced ovarian cancer
Gynecol Oncol
(2003)
E.C. Kohn et al.
Molecular therapeutics: promise and challenges
Semin Oncol
(2004)
A. Bodo et al.
The role of multidrug transporters in drug availability, metabolism and toxicity
Toxicol Lett
(2003)
S. Pradhan et al.
Mammalian DNA (cytosine-5) methyltransferases and their expression
Clin Immunol
(2003)
S. Xie et al.
Cloning, expression and chromosome locations of the human DNMT3 gene family
Gene
(1999)
M. Ehrlich et al.
Satellite DNA hypomethylation in karyotyped Wilms tumors
Cancer Genet Cytogenet
(2003)
G.Z. Qu et al.
Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16
Cancer Genet Cytogenet
(1999)

G. Qu et al.

Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential

Mutat Res

(1999)

A. Ahluwalia et al.

DNA methylation in ovarian cancer: II, expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells

Gynecol Oncol

(2001)

K.P. Nephew et al.

Epigenetic gene silencing in cancer initiation and progression

Cancer Lett

(2003)

L. Gao et al.

Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family

J Biol Chem

(2002)

O. Witt et al.

Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin

Blood

(2003)

P.G. McCaffrey et al.

Induction of gamma-globin by histone deacetylase inhibitors

Blood

(1997)

H. Cao et al.

Induction of human gamma globin gene expression by histone deacetylase inhibitors

Blood

(2004)

J.R. Jass et al.

Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability

Eur J Cancer

(2002)

P.S. Yan et al.

Applications of CpG island microarrays for high-throughput analysis of DNA methylation

J Nutr

(2002)

A. Ahluwalia et al.

DNA methylation and ovarian cancer: I, analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization

Gynecol Oncol

(2001)

L.J. Rush et al.

Restriction landmark genomic scanning for DNA methylation in cancer: past, present, and future applications

Anal Biochem

(2002)

D.M. Parkin et al.

Estimating the world cancer burden: Globocan 2000

Int J Cancer

(2001)

T. Kaku et al.

Histological classification of ovarian cancer

Med Electron Microsc

(2003)

R. Agarwal et al.

Ovarian cancer: strategies for overcoming resistance to chemotherapy

Nat Rev Cancer

(2003)

P.E. Schwartz

Diagnosis and treatment of epithelial ovarian cancer

Minerva Ginecol

(2003)

R.T. Greenlee et al.

Cancer statistics,2001

CA Cancer J Clin

(2001)

Z.H. Siddik

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Oncogene

(2003)

P.F. Conte et al.

Second-line treatment and consolidation therapies in advanced ovarian cancer

Int J Gynecol Cancer

(2001)

C.M. Ulrich et al.

Cancer pharmacogenetics: polymorphisms, pathways and beyond

Nat Rev Cancer

(2003)

M.A. Shah et al.

Cell cycle-mediated drug resistance: an emerging concept in cancer therapy

Clin Cancer Res

(2001)

T. Fojo et al.

Strategies for reversing drug resistance

Oncogene

(2003)

M. Sakamoto et al.

Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray

Hum Cell

(2001)

D.E. Lamendola et al.

Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line

Cancer Res

(2003)

P.A. Jones

DNA methylation and cancer

Oncogene

(2002)

C. Plass et al.

DNA methylation, imprinting and cancer

Eur J Hum Genet

(2002)

P.M. Vertino et al.

DNMT1 is a component of a multiprotein DNA replication complex

Cell Cycle

(2002)

S.B. Baylin et al.

Alterations in DNA methylation: a fundamental aspect of neoplasia

Adv Cancer Res

(1998)

A. Narayan et al.

Hypomethylation of pericentromeric DNA in breast adenocarcinomas

Int J Cancer

(1998)

C.M. Tuck-Muller et al.

DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients

Cytogenet Cell Genet

(2000)

K.D. Robertson

DNA methylation, methyltransferases, and cancer

Oncogene

(2001)

K.D. Robertson et al.

The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors

Nucleic Acids Res

(1999)

M.S. Bartolomei et al.

Genomic imprinting in mammals

Annu Rev Genet

(1997)

E. Heard et al.

X-chromosome inactivation in mammals

Annu Rev Genet

(1997)

T.H. Bestor

The host defence function of genomic methylation patterns

Novartis Found Symp

(1998)

P. Marks et al.

Histone deacetylases and cancer: causes and therapies

Nat Rev Cancer

(2001)

A.J. de Ruijter et al.

Histone deacetylases(HDACs): characterization of the classical HDAC family

Biochem J

(2003)

R. Claus et al.

Epigenetic targets in hematopoietic malignancies

Oncogene

(2003)

T. Kalebic

Epigenetic changes: potential therapeutic targets

Ann N Y Acad Sci

(2003)

M.V. Blagosklonny et al.

Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity

Mol Cancer Ther

(2002)

J.W. Han et al.

Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin

Cancer Res

(2000)

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: Supported by NCI grant CA05289 and Cancer Research UK grant C536.

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AJOG ReviewThe epigenetics of ovarian cancer drug resistance and resensitization

Section snippets

DNA methylation

Epigenetic markers as prognostic indicators

Conclusions

Acknowledgment

Am J Obstet Gynecol

Gynecol Oncol

Semin Oncol

Gynecol Oncol

Semin Oncol

Toxicol Lett

Clin Immunol

Gene

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Mutat Res

Gynecol Oncol

Cancer Lett

J Biol Chem

Blood

Blood

Blood

Eur J Cancer

J Nutr

Gynecol Oncol

Anal Biochem

Estimating the world cancer burden: Globocan 2000

Int J Cancer

Histological classification of ovarian cancer

Med Electron Microsc

Ovarian cancer: strategies for overcoming resistance to chemotherapy

Nat Rev Cancer

Diagnosis and treatment of epithelial ovarian cancer

Minerva Ginecol

Cancer statistics,2001

CA Cancer J Clin

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Oncogene

Second-line treatment and consolidation therapies in advanced ovarian cancer

Int J Gynecol Cancer

Cancer pharmacogenetics: polymorphisms, pathways and beyond

Nat Rev Cancer

Cell cycle-mediated drug resistance: an emerging concept in cancer therapy

Clin Cancer Res

Strategies for reversing drug resistance

Oncogene

Analysis of gene expression profiles associated with cisplatin resistance in human ovarian cancer cell lines and tissues using cDNA microarray

Hum Cell

Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line

Cancer Res

DNA methylation and cancer

Oncogene

DNA methylation, imprinting and cancer

Eur J Hum Genet

DNMT1 is a component of a multiprotein DNA replication complex

Cell Cycle

Alterations in DNA methylation: a fundamental aspect of neoplasia

Adv Cancer Res

Hypomethylation of pericentromeric DNA in breast adenocarcinomas

Int J Cancer

DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients

Cytogenet Cell Genet

DNA methylation, methyltransferases, and cancer

Oncogene

The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors

Nucleic Acids Res

Genomic imprinting in mammals

Annu Rev Genet

X-chromosome inactivation in mammals

Annu Rev Genet

The host defence function of genomic methylation patterns

Novartis Found Symp

Histone deacetylases and cancer: causes and therapies

Nat Rev Cancer

Histone deacetylases(HDACs): characterization of the classical HDAC family

Biochem J

Epigenetic targets in hematopoietic malignancies

Oncogene

Epigenetic changes: potential therapeutic targets

AJOG Review
The epigenetics of ovarian cancer drug resistance and resensitization