Different Involvement of DNA Methylation and Histone Deacetylation in the Expression of Solute-Carrier Transporters in 4 Colon Cancer Cell Lines

Ikehata, Mika; Iwakawa, Seigo

doi:10.1248/bpb.35.301

Cited by 25 publications

(20 citation statements)

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“…17) In our previous study, it was found that 4 CRC cell lines (SW48 and HCT116 cells as MSI; HT29 and SW480 cells as microsatellite stable, MSS) 18) underwent different epigenetic changes of several solute carrier transporters, which have been reported to be involved in the transport of anticancer drugs such as 5-FU. 19) In this study, we examined the potential of epigenetic modifiers as chemo-sensitizers in combination with chemotherapeutic drugs in the 4 CRC cell lines used in our previous study. 19) Different epigenetic modifiers were used, including DAC, AC and zebularine (Zeb) as DNMT inhibitors and TSA, SAHA and valproic acid (VPA) as HDAC inhibitors.…”

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“…19) In this study, we examined the potential of epigenetic modifiers as chemo-sensitizers in combination with chemotherapeutic drugs in the 4 CRC cell lines used in our previous study. 19) Different epigenetic modifiers were used, including DAC, AC and zebularine (Zeb) as DNMT inhibitors and TSA, SAHA and valproic acid (VPA) as HDAC inhibitors. The results obtained from this study about the effects of epigenetic modification on the cytotoxicity induced by anticancer drugs will provide information to help understand how to incorporate epigenetic modifiers into the current anticancer armamentarium.…”

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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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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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“…SLC19A3 encodes the thiamine transporter expressed at the apical surface of polarized cells (35). SLC19A3 mRNA expression has been shown to be downregulated by DNA methylation in colon cancer cell lines (36). DLEC1 has been demonstrated to act as a tumor suppressor gene in the tumorigenesis and progression of numerous types of carcinoma, such as multiple lymphomagenesis, and thus it may serve as a non-invasive tumor marker (37).…”

Section: Discussionmentioning

confidence: 99%

CDKN2B, SLC19A3 and DLEC1 promoter methylation alterations in the bone marrow of patients with acute myeloid leukemia during chemotherapy

Hong

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated that promoter hypermethylation of tumor suppressor genes contributes to the occurrence and development of acute myeloid leukemia (AML). However, the association of DNA methylation with chemotherapeutic outcomes remains unknown. In the present study, 15 patients with AML were recruited, and the promoter methylation status of cyclin-dependent kinase inhibitor 2B (CDKN2B), solute carrier family 19 member 3 (SLC19A3) and deleted in lung and esophageal cancer 1 (DLEC1) genes was examined prior to and following various chemotherapeutic regimens in order to identify any alterations. The results suggested that chemotherapy-induced hypermethylation of CDKN2B and DLEC1 may be specific to males and females, respectively, and that there were no alterations in SLC19A3 methylation following chemotherapy. These results may provide an improved understanding of gene methylation to guide the development of an individualized chemotherapy for AML. Due to the complexity of AML and the wide range of treatment types, future studies with a larger sample size are required in order to verify the results of the present investigation.

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“…22) Briefly, total RNA was extracted from HCT116 cells by the spin column method using the RNeasy Mini Kit (QIAGEN, Valencia, CA, U.S.A.), including on-column DNA digestion using the RNase-free DNase set (QIAGEN). Total RNA was reverse-transcribed into cDNA using a ReverTra Ace qPCR Kit (TOYOBO, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…12) The DAC analogue azacytidine was found to decrease the global level of DNA methylation and to downregulate DNMT1 and DNMT3a gene transcription in HCT116 cells at 3 to 4 d. 21) We also examined the DNA demethylating effects of DAC on various solute carrier (SLC) transporters in 4 human colon cancer cell lines, and found that DAC increased the mRNA levels of four SLC transporters examined in HCT116 cells. 22) Since DAC has various effects on DNA demethylation and cell survival in HCT116 cells, DAC may be taken up intracellularly to markedly high levels, and this DAC uptake may be related to the effects of DAC on DNA demethylation and cell survival in HCT116 cells. In the present study, we attempted to characterize the cellular uptake of uridine and DAC, and showed that DAC was mainly taken up by ENT1, similar to uridine, a typical substrate for ENT1, in HCT116 cells.…”

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Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells

Hosokawa

Iwakawa

2015

Biological & Pharmaceutical Bulletin

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DNA hypermethylation, an epigenetic change that silences gene expression without altering nucleotide sequences, plays a critical role in the formation and progression of colorectal cancers as well as in the acquisition of drug resistance. Decitabine (DAC), a DNA methyltransferase 1 inhibitor of nucleoside analogues, has been shown to restore gene expression silenced by hypermethylation. In the present study, the mechanisms underlying both uridine and DAC uptake were examined in the human colon cancer cell line HCT116. Real-time polymerase chain reaction analysis revealed that ENT1 mRNA was the most abundant among the nucleoside transporters examined in HCT116 cells. The ENT1 protein was detected in the membrane fraction, as determined by Western blotting. The uptake of uridine or DAC was time-and concentration-dependent, but also Na -independent. The uptake of these agents was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENTs), and was also decreased in cells treated with ENT1 small interfering RNA. The uptake of both uridine and DAC was inhibited by uridine, cytidine, adenosine, or inosine, while that of DAC was also inhibited by thymidine. The expression of MAGEA1 mRNA, the DNA of which was methylated in HCT116 cells, was increased by DAC treatment, and this increment was attenuated by concomitant treatment with NBMPR. The IC 50 value of DAC was also increased in the presence of NBMPR. These results suggest that DAC is mainly taken up by ENT1 and that this uptake is one of the key determinants of the activity of DAC in HCT116 cells. Key words equilibrative nucleoside transporter; decitabine; uridineColorectal cancer is the second most common cancer in females and third most common cancer in males worldwide including Japan.1,2) Approximately 600000 people die from this cancer in the world each year. The majority of colon cancers arise sporadically, and the deficient expression of DNA repair genes has frequently been observed in these sporadic colorectal cancers. Previous studies reported that this deficient expression was often due to epigenetic alterations that did not include changes in the DNA sequence.3,4) DNA hypermethylation is one of the epigenetic alterations in colorectal cancers that occur in the CG-rich regions of the promoter region of protein-coding genes. These changes cause the transcriptional silencing of cancer-related genes such as tumor suppressor genes.3) DNA hypermethylation also plays a critical role in the acquisition of drug resistance by colorectal cancers. For example, promoter methylation of the DNA mismatch repair gene, human MLH1, has been associated with the loss of DNA mismatch repair and resistance to 5-FU in colon cancer cell lines or to cisplatin, carboplatin, temozolomide, or epirubicin in human tumor xenografts. 5,6) Decitabine (5-aza-2′-deoxycytidine; DAC) is a DNA methyltransferase 1 inhibitor that restores gene expression silenced as a result of DNA hypermethylation. 7,8) Several studies have demonstrated that...

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Different Involvement of DNA Methylation and Histone Deacetylation in the Expression of Solute-Carrier Transporters in 4 Colon Cancer Cell Lines

Cited by 25 publications

References 38 publications

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

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

CDKN2B, SLC19A3 and DLEC1 promoter methylation alterations in the bone marrow of patients with acute myeloid leukemia during chemotherapy

Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells

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