Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts

Sperotto, Nathalia Denise de Moura; Silva, Rodrigo Braccini Madeira; Perelló, Marcia Alberton; Borsoi, Ana Flávia; Dadda, Adílio da Silva; Roth, Candida Deves; Freitas, Raquel Dal Sasso; Souza, Ana Paula Duarte de; Freitas, Deise do Nascimento de; Picada, Jaqueline Nascimento; Sousa, José da Silva; Nabinger, Débora Dreher; Altenhofen, Stefani; Bonan, Carla Denise; Rodrigues-Junior, Valnês S.; Bizarro, Cristiano Valim; Basso, Luiz Augusto; Machado, Pablo

doi:10.1016/j.biopha.2021.111672

Cited by 2 publications

(4 citation statements)

References 41 publications

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“…We have preliminary results that should be further validated, indicating that sex-related disparities may explain why female mice show the most significant tumor volume reduction in the 5-FU single treatment and in combination with mannose, while tumors in male mice were not affected by the combination treatment. On the other hand, a study showed that male mice were more sensitive to the 5-FU treatment than female mice [ 31 ]. However, the authors used a different mouse strain (BALB/c nude mice) where tumors grew more in male than in female animals, and mice were administered a three times higher dose of 5-FU [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, a study showed that male mice were more sensitive to the 5-FU treatment than female mice [ 31 ]. However, the authors used a different mouse strain (BALB/c nude mice) where tumors grew more in male than in female animals, and mice were administered a three times higher dose of 5-FU [ 31 ]. Thus, the mannose anti-tumor effect in CRC may be affected by sex, which remains to be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

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Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy

Hadeethi

El-Baba

Araji

et al. 2023

Cancers

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Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy

Hadeethi

El-Baba

Araji

et al. 2023

Cancers

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“…TYMP is responsible for systemic tumor-specific CD8+ cell exhaustion and abrogates adoptive dendritic cell therapy efficacy in a preclinical CRC model, which depicts systemic T-cell loss and reduced ACT or immunotherapy efficacy observed in animal models with advanced CRC. Therefore, TYMP has been the target for alleviating immunosuppression in CRC tumors ( 20 , 21 , 23 – 25 ). Here, we found that tipiracil hydrochloride, a small molecular inhibitor of TYMP, induces an ER stress response that ultimately leads to the production of DAMPs (CRT, HMGB1, ATP) and primes ICD in vitro and in vivo in an experimental model of CRC.…”

Section: Discussionmentioning

confidence: 99%

“…Increased TYMP expression suppresses the immune response via increased secretion of IL-10 in the TME, which inhibits the effector functions of DCs and the Th1 cytokine profile (19). TYMPtargeted therapy using small-molecule TYMP inhibitors (i.e., trifluridine, tipiracil, or TAS-102) has been shown to cause tumor regression in a large number of preclinical gastrointestinal tumor models (20)(21)(22)(23) and is under evaluation as monotherapy (NCT03974594) and in combination with other therapeutic regimens in a large number of clinical trials (24)(25)(26). While these studies are insightful, the mechanisms mediating the therapeutic response in CRC for anti-TYMP alone or in combination with cell therapies, such as adoptive DC vaccines, remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Targeting thymidine phosphorylase alleviates resistance to dendritic cell immunotherapy in colorectal cancer and promotes antitumor immunity

et al. 2022

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T-cell exhaustion plays a pivotal role in the resistance of microsatellite-stable colorectal cancer (CRC) to immunotherapy. Identifying and targeting T-cell exhaustion-activating mechanisms is a promising strategy to augment the effects of immunotherapy. Here, we found that thymidine phosphorylase (TYMP) plays a decisive role in inducing systemic T-cell exhaustion and abrogating the efficacy of dendritic cell (DC) therapy in a CRC model. Targeting TYMP with tipiracil hydrochloride (TPI) induces immunological cell death (ICD). The combined effects of TPI and imiquimod-activated DCs turn CT26 tumors into immunologically ‘hot’ tumors by inducing ICD in vivo. High-dimensional cytometry analysis revealed T-cell and IFN-γ dependency on the therapeutic outcome. In addition, chemoimmunotherapy converts intratumoral Treg cells into Th1 effector cells and eliminates tumor-associated macrophages, resulting in higher cytotoxic T lymphocyte infiltration and activation. This effect is also associated with the downregulation of PD-L1 expression in tumors, leading to the prevention of T-cell exhaustion. Thus, cooperative and cognitive interactions between dendritic cells and immunogenic cell death induced by therapy with TPI promote the immune response and tumoricidal activities against microsatellite stable colorectal cancer. Our results support TYMP targeting to improve the effects of DC immunotherapy and outcomes in CRC.

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Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts

Cited by 2 publications

References 41 publications

Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy

Mannose Inhibits the Pentose Phosphate Pathway in Colorectal Cancer and Enhances Sensitivity to 5-Fluorouracil Therapy

Targeting thymidine phosphorylase alleviates resistance to dendritic cell immunotherapy in colorectal cancer and promotes antitumor immunity

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