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

Cited by 118 publications

(91 citation statements)

References 191 publications

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“…However, past studies with such agents were associated with extensive toxicity and minimal efficacy. 39,40 Hence, it is crucial to obtain better insight into their mode of action in order to increase efficacy and reduce non-specific toxicity.…”

Section: Discussionmentioning

confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumorsuppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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“…1) CRC treatment strategies are highly dependent on tumor stage. Metastatic CRC (stage IV) is treated with combined chemotherapy, including 5-fluorouracil (5-FU) plus either irinotecan (CPT-11) or oxaliplatin (L-OHP).…”

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confidence: 99%

“…7) In vitro experiments and animal models have shown that DNMT and HDAC inhibitors have anti-tumor activities in CRC. 1) However, minor efficacy of epigenetic modifiers has been reported in solid tumors, including CRC in humans. 1,8) On the other hand, epigenetic mechanisms have been reported to trigger resistance to conventional anticancer drugs in CRC.…”

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confidence: 99%

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Different Effects of Epigenetic Modifiers on the Cytotoxicity Induced by 5-Fluorouracil, Irinotecan or Oxaliplatin in Colon Cancer Cells

Ikehata

Ogawa

Yamada

et al. 2014

Biological & Pharmaceutical Bulletin

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We investigated the effects of epigenetic modifiers such as DNA methyltransferase (DNMT) or histone deacetylase (HDAC) inhibitors on the cytotoxicity induced by 3 anticancer drugs (5-fluorouracil (5-FU), irinotecan (CPT-11) or its active form SN38, and oxaliplatin (L-OHP)) in human colorectal cancer (CRC) cells. Cytotoxicity in 4 CRC cell lines (HT29, SW480, SW48 and HCT116) was examined by colorimetric assay after drug treatment for 72 h. The effects of drug combinations were analyzed by an isobologram method. SW480 cells showed the lowest sensitivity to cytotoxicity induced by the anticancer drugs among the 4 CRC cell lines. In SW480 cells, DNMT inhibitors, such as decitabine (DAC), azacytidine and zebularine (Zeb), showed synergic effects on the cytotoxicity induced by anticancer drugs except for SN-38 plus Zeb, while HDAC inhibitors, trichostatin A, suberoylanilide hydroxamic acid and valproic acid, showed antagonistic effects. DAC showed the most potent synergic effects among the epigenetic modifiers studied. Thus, we examined whether the synergic effect of DAC is observed in other different CRC cell lines, HT29, SW48 and HCT116 cells. In all 4 CRC cell lines, the cytotoxicity of L-OHP was enhanced in a synergic manner by cotreatment with DAC. However, synergic effects of DAC with 5-FU or CPT-11 (SN-38) were not observed in 4 CRC cell lines.Key words DNA methyltransferase inhibitor; synergism; colorectal cancer; isobologram; histone deacetylase inhibitor Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the world.1) CRC treatment strategies are highly dependent on tumor stage. Metastatic CRC (stage IV) is treated with combined chemotherapy, including 5-fluorouracil (5-FU) plus either irinotecan (CPT-11) or oxaliplatin (L-OHP). Recently, it has been reported that combined chemotherapy plus biological agents (anti-angiogenic or antiepidermal growth factor receptor molecules) increased stage IV patients' median survival period.2) Despite many therapeutic options, an efficient drug combination remains to be found for CRC patients. In addition, tailored therapy for each CRC patient is still a challenge.It is well-established that epigenetic alterations such as DNA methylation and histone modifications play a crucial role in the initiation and progression of cancer, including CRC. Unlike genetic alterations, epigenetic alterations are reversible and can be targeted by epigenetic modifiers.3) Epigenetic modifiers such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors have been administered for several years and have been evaluated as a treatment approach for a variety of cancers in the United States. DNMT inhibitors, such as decitabine (5-aza-2′-deoxycytidine; DAC) and 5-azacytidine (AC), are being used for the treatment of myelodysplastic syndromes (MDS), but the efficacy is variable. 4,5) In addition, DAC is used usually for patients with acute myeloid leukemia who are not candidates for standard remission, including chemotherapy. 6) On the other h...

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“…Epigenetic modifications are implicated in the progression of chemoresistance [112]. They bring about changes in gene expression that are autonomous of changes in DNA sequence and persevere over numerous cell divisions.…”

Section: Pharmacoepigenomicsmentioning

confidence: 99%

Acquired and Intrinsic Resistance to Colorectal Cancer Treatment

Briffa¹,

Langdon²,

Grech³

et al. 2018

Colorectal Cancer - Diagnosis, Screening and Management

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First line therapy for colorectal cancer (CRC) is usually fluoropyrimidine monotherapy and oxaliplatin, or irinotecan-based therapy. Additionally, targeted therapies such as bevacizumab, aflibercept, ramucirumab, regorafenib, cetuximab and panitumumab are indicated in combination with chemotherapy in metastatic CRC. Resistance of CRC to treatment is the principal rationale for treatment failure. Resistance can be intrinsic (primary resistance) or acquired (secondary resistance). Here, we discuss the classical model of resistance, which focuses primarily on mechanisms involving alterations in drug metabolism, increased drug efflux, secondary mutations in drug targets, inactivation of apoptotic pathways, p53 and DNA damage repair. Other resistance mechanisms, including the Warburg effect, cancer stem cells, intra-tumor heterogeneity and pharmacoepigenomic mechanisms will also be discussed. We conclude the chapter with a systems medicine approach to predict response to treatment for the discovery and validation of predictive biomarkers that are urgently needed.

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

Cited by 118 publications

References 191 publications

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Different Effects of Epigenetic Modifiers on the Cytotoxicity Induced by 5-Fluorouracil, Irinotecan or Oxaliplatin in Colon Cancer Cells

Acquired and Intrinsic Resistance to Colorectal Cancer Treatment

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