Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies

Crea, Francesco; Nobili, Stefania; Paolicchi, Elisa; Perrone, Gabriele; Napoli, Cristina; Landini, Ida; Danesi, Romano; Mini, Enrico

doi:10.1016/j.drup.2011.08.001

« PreviousDrug Resistance Updates
Volume 14, Issue 6 , Pages 280-296, December 2011

Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies

Francesco Crea
- Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy
- These authors contributed equally to this work.
Stefania Nobili
- Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy
- These authors contributed equally to this work.
Elisa Paolicchi
- Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy
Gabriele Perrone
- Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy
Cristina Napoli
- Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy
Ida Landini
- Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy
Romano Danesi
- Division of Pharmacology, Department of Internal Medicine, University of Pisa, Pisa, Italy
- Corresponding author. Tel.: +39 050 992632.
Enrico Mini
- Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy
- Corresponding author. Tel.: +39 055 4271305; fax: +39 055 4271280.

Received 15 July 2011; received in revised form 9 August 2011; accepted 13 August 2011. published online 28 September 2011.

Highlights

► Colorectal cancer (CRC) is the second cause of cancer-related deaths in the world. ► Despite therapeutic advancements, CRC drug resistance is the main cause of treatment failure. ► Epigenetics may play a key role in chemoresistance. ► Epigenetic mechanisms of resistance to 5-FU, irinotecan and oxaliplatin in CRC are described. ► Drug resistance modulation by epigenetic drugs may contribute to improve therapeutic outcome.

Abstract

Colorectal cancer is the second leading cause of cancer-related deaths in the world. Despite many therapeutic opportunities, prognosis remains dismal for patients with metastatic disease, and a significant portion of early-stage patients develop recurrence after chemotherapy. Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. In the present review, we summarize epigenetic mechanisms triggering resistance to three commonly used agents in colorectal cancer: 5-fluorouracil, irinotecan and oxaliplatin. Those epigenetic biomarkers may help stratify colorectal cancer patients and develop a tailored therapeutic approach. In addition, epigenetic modifications are reversible through specific drugs: histone-deacetylase and DNA-methyl-transferase inhibitors. Preclinical studies suggest that these drugs may reverse chemoresistance in colorectal tumors. In conclusion, an epigenetic approach to colorectal cancer chemoresistance may pave the way to personalized treatment and to innovative therapeutic strategies.

Keywords: Colorectal cancer, Epigenetics, Chemoresistance, 5-Fluorouracil, Irinotecan, Oxaliplatin, Histone deacetylase inhibitors, DNA-methyl-transferase inhibitors