Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

Sharma, Anup; Vatapalli, Rajita; Abdelfatah, Eihab; McMahon, K. Wyatt; Kerner, Zachary; Guzzetta, Angela A.; Singh, Jasvinder; Zahnow, Cynthia A.; Baylin, Stephen B.; Yerram, Sashidhar R.; Hu, Yue; Azad, Nilofer S.; Ahuja, Nita

doi:10.1371/journal.pone.0176139

Cited by 35 publications

(27 citation statements)

References 39 publications

(45 reference statements)

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“…Earlier studies stated that DAC and AZA have pro-apoptotic activities in myeloid leukaemia cells [ 58 , 59 ], neoplastic mast cells [ 60 ] and have the ability sensitize colorectal cancer cells to apoptosis induction by chemotherapy or immunotherapy [ 61 , 62 ]. To elucidate whether the pro-apoptotic activity of DAC and AZA could be enhanced by vitamin C, combined treatments in HCT116 cells were assessed by Annexin V/propidium iodide staining and flow cytometric analysis (Figure 9 ).…”

Section: Resultsmentioning

confidence: 99%

Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells

et al. 2018

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Epigenetic silencing of tumour suppressor genes is a key hallmark of colorectal carcinogenesis. Despite this, the therapeutic potential of epigenetic agents capable of reactivating these silenced genes remains relatively unexplored. Evidence has shown the dietary antioxidant vitamin C (ascorbate) acts as an inducer of the ten-eleven translocation (TET) dioxygenases, an enzyme family that catalyses a recently described mechanism of DNA demethylation linked to gene re-expression. In this study, we set out to determine whether vitamin C can enhance the known anti-neoplastic actions of the DNA-demethylating agents decitabine (DAC) and azacytidine (AZA) in colorectal cancer cells. Administration of vitamin C alone significantly enhanced global levels of 5-hydroxymethyl-2’-deoxycytidine (5-hmdC), without altering 5-methyl-2’-deoxycytidine (5-mdC), as would be expected upon the activation of TET dioxygenases. Concomitant treatment of vitamin C with either AZA or DAC resulted in an unexpectedly high increase of global 5-hmdC levels, one that administration of any these compounds alone could not achieve. Notably, this was also accompanied by increased expression of the tumour suppressor p21 (CDKN1A), and a significant increase in apoptotic cell induction. Our in vitro data leads us to hypothesize that the reactivation of genes in colorectal cancer cells by AZA or DAC can be improved when the 5-hmdC levels are simultaneously increased by the TET activator vitamin C. The dual administration of demethylating agents and vitamin C to colorectal cancer patients, a demographic in which vitamin C deficiencies are common, may improve responses to epigenetic therapies.

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Section: Resultsmentioning

confidence: 99%

Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells

et al. 2018

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“…For this trial we targeted a patients with mCRC based upon work in our group demonstrating the ability of DNMTi to reverse irinotecan resistance in both resistant colon cancer cell lines and mouse models (10,22). There is no well-agreed upon mechanism that has explained irinotecan resistance (23,24).…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical CRC models, DNMTis can induce re-expression of tumor suppressor genes (9). Our group has reported DNMTi can both induce sensitivity and reverse chemoresistance to irinotecan in in vitro and in vivo models (10).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan

Lee

Wang

Zahurak

et al. 2018

Clinical Cancer Research

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Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan. In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m; DL -1: guadecitabine 30 mg/m; DL -1G: guadecitabine 30 mg/m with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m with GFS]. Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and -1G), biliary drain infection (DL -1), colonic obstruction (DL -1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment. We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m and irinotecan 125 mg/m with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.

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“…In fact, tumor suppressor genes were found re-expressed by DNA methyltransferase enzyme inhibitors (DNMTi) in colorectal cancer cell lines (Bosch et al, 2016). In line with this, DNMTinhibitors-reversed irinotecan chemotherapy resistance in colorectal cancer models, in vitro and in vivo (Sharma et al, 2017). Before using DAC as an external modulator, we analyzed DC T = C T (EDN1)-C T (GAPDH) (C T ; threshold cycle: the PCR cycle at which the fluorescent signal of the reporter dye crosses an arbitrarily placed threshold).…”

Section: Discussionmentioning

confidence: 77%

Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

et al. 2020

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Targeting of endothelin system genes is a promising strategy in cancer therapy. The modulation of these genes was explored in a model of colorectal cancer (CRC) liver metastasis and in a panel of CRC tumor cell lines that were exposed to the demethylating agent decitabine. The CC531 rat model mimicking CRC liver metastasis was used for tumor cell re-isolation and analysis of the endothelin system genes and DNA methyltransferases (DNMTs) by microarray. To mimic the effects caused by methylation changes, a panel of seven CRC cell lines was treated with the demethylating agent decitabine. Three genes of the endothelin system were potently modulated at messenger RNA (mRNA) level in rat CC531 cells during liver colonization. The concomitant decrease of two DNMTs suggested an influence from altered methylation. Changes in gene expression were also accomplished by exposure of CRC cells to the demethylating agent decitabine, when using daily low concentrations for 3 days, with minimal cytotoxic effects. Sensitive human SW480 cells showed an almost 100fold upregulation of endothelin-1 mRNA compared to untreated cells. This, however, was different in LS174T cells, which showed no significant increase in gene expression although the methylation levels were significantly decreased at a variety of corresponding loci. We suggest that the mechanism induced by methylation on gene expression in metastatic CRC cells can be compromised. The results question the overall success of treating metastatic CRC by methylation inhibitors.

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Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

Cited by 35 publications

References 39 publications

Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells

Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells

A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan

Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

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