Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays

Rothkamm, Kai; Christiansen, Sabrina; Rieckmann, Thorsten; Horn, Michael; Frenzel, Thorsten; Brinker, Alexandra; Schumacher, Udo; Stein, Alexander; Petersen, Cordula; Burdak‐Rothkamm, Susanne

doi:10.1016/j.canlet.2020.08.038

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…In addition, we also showed that chemoradiotherapy with FTD/TPI, MK1775, and radiation had a good antitumor effect in vivo. FTD/TPI monotherapy has shown some good positive but moderate effect on sensitivity to radiotherapy in metastatic colon cancer 35 . Together with that, MK1775 was also proven to enhance the sensitivity to radiotherapy in ESCC 36 .…”

Section: Discussionmentioning

confidence: 92%

“…FTD/TPI monotherapy has shown some good positive but moderate effect on sensitivity to radiotherapy in metastatic colon cancer. 35 Together with that, MK1775 was also proven to enhance the sensitivity to radiotherapy in ESCC. 36 Therefore, we believe that this combination of FTD/TPI and MK1775 can be a good candidate to improve the outcome of radiotherapy effectiveness.…”

Section: Discussionmentioning

confidence: 93%

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Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

Nguyen Vu,

Kikuchi,

Ohashi

et al. 2023

Cancer Science

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Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single‐strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin‐dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho‐histone H3 (p‐hH3)‐positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p‐hH3‐positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine‐mediated DNA damage, namely DNA double‐strand breaks, as shown by increased γ‐H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC‐derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 93%

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

Nguyen Vu,

Kikuchi,

Ohashi

et al. 2023

Cancer Science

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“…Further toxicity experiments revealed that the optimal cell concentration at which AZD6738 acts is 0.5 µM. The IC 50 for FTD was 70 µM in HT29 cells and 5 µM in HCT116 cells ( 33 , 34 ).…”

Section: Resultsmentioning

confidence: 99%

AZD6738 promotes the tumor suppressive effects of trifluridine in colorectal cancer cells

et al. 2023

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Ataxia telangiectasia and Rad3-related (ATR) is a kinase that repairs DNA damage. Although inhibitors that selectively target ATR have been developed, their effectiveness in colorectal cancer has not been widely reported. The present study hypothesized that anticancer agents that effectively act in the S phase before the G 2 /M checkpoint may be ideal agents for concomitant use with ATR inhibitors, which act at the G 2 /M checkpoint. Therefore, the present study examined the combined effects of AZD6738, an ATR inhibitor, and trifluridine (FTD), which acts in the S phase and has a high DNA uptake rate. In vitro cell viability assays, flow cytometry and western blotting were performed to evaluate cell viability, and changes in cell cycle localization and protein expression. The results revealed that in colorectal cancer cells, the combination of AZD6738 and FTD inhibited cell viability, cell cycle arrest at the G 2 /M checkpoint and Chk1 phosphorylation, and increased apoptotic protein expression levels more than that when treated with FTD alone. HT29, a BRAF-mutant cell line known to be resistant to anticancer drugs, was used to induce tumors in vivo. Since FTD does not have sufficient efficacy when administered orally, it was mixed with tipiracil to prevent degradation; this mixture is known as TAS-102. TAS-102 alone exerted minimal tumor suppressive effects; however, when used in combination with AZD6738, tumor suppression was observed, suggesting that AZD6738 may increase the effectiveness of a weakly effective drug. Although ATR inhibitors are effective against p53 mutants, the present study demonstrated that these inhibitors were also effective against the p53 wild-type HCT116 colorectal cancer cell line. In conclusion, combination therapy with AZD6738 and FTD enhanced the inhibition of tumor proliferation in vitro and in vivo. In the future, we aim to investigate the potentiating effect of AZD6738 on 5-fluouracil-resistant cell lines that are difficult to treat.

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“…In an ongoing clinical trial (NCT04177602), the preclinical experimental result demonstrates radio chemotherapy with FTD/TPI for advanced rectal cancer would be evaluated. 91 A possible anticancer drug has been discovered in the form of β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT). Conventional radiation therapy typically has a therapeutic effect by the indirect action of free radicals created by the radiolysis of water, followed by the oxidation of biomolecules.…”

Section: Radiosensitizers As Therapeutic Strategy In Rectal Cancermentioning

confidence: 99%

Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review

Jain,

Nagainallur Ravichandran,

Murali Kumar

et al. 2024

Cancer Biology & Therapy

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Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as – the PI3K/AKT pathway, Wnt/β-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.

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Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays

Cited by 9 publications

References 31 publications

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

AZD6738 promotes the tumor suppressive effects of trifluridine in colorectal cancer cells

Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review

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