Pyrimethamine inhibits cell growth by inducing cell senescence and boosting CD8+ T-cell mediated cytotoxicity in colorectal cancer

Dong, Haiyan; Hu, Limei; Li, Weiqian; Shi, Mengchen; He, Lingyuan; Wang, Chen; Hu, Yijia; Wen, Chuangyu; Liu, Huanliang; Yang, Xiangling

doi:10.1007/s11033-022-07262-y

Cited by 8 publications

(5 citation statements)

References 39 publications

(44 reference statements)

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“…Recent findings by Marín et al [ 71 ] support our results, as they demonstrated that senescent melanoma cells stimulate the activation of tumor-reactive CD8 + tumor-infiltrating T cells, promoting anticancer immune surveillance. A correlation between induced cancer cell senescence and infiltration of CD8 + cells was also recently demonstrated in colorectal cancer after pyrimethamine treatment [ 72 ].…”

Section: Discussionmentioning

confidence: 80%

Melanoma Cell Reprogramming and Awakening of Antitumor Immunity as a Fingerprint of Hyper-Harmonized Hydroxylated Fullerene Water Complex (3HFWC) and Hyperpolarized Light Application In Vivo

et al. 2023

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In our recent study, we showed that in vitro treatment of melanoma cells with hyperpolarized light (HPL) as well as with the second derivative of fullerene, hyper-harmonized hydroxylated fullerene water complex (3HFWC) reduced viability of cells by decreasing their proliferative capacity and inducing senescence and reprogramming towards a normal, melanocytic phenotype. Therefore, we wanted to determine whether these effects persisted in vivo in the syngeneic mouse melanoma model with a combined treatment of HPL irradiation and 3HFWC per os. Our results demonstrated the potent antitumor effects of 3HFWC nanosubstance assisted by HPL irradiation. These effects were primarily driven by the stimulation of melanoma cell growth arrest, the establishment of a senescent phenotype, and melanocytic differentiation on the one hand, and the awakening of the antitumor immune response on the other. In addition, the combined treatment reduced the protumorigenic activity of immune cells by depleting T regulatory cells, myeloid-derived suppressors, and M2 macrophages. The support of the 3HFWC substance by HPL irradiation may be the axis of the new approach design based on tumor cell reprogramming synchronized with the mobilization of the host’s protective immune response.

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Section: Discussionmentioning

confidence: 80%

Melanoma Cell Reprogramming and Awakening of Antitumor Immunity as a Fingerprint of Hyper-Harmonized Hydroxylated Fullerene Water Complex (3HFWC) and Hyperpolarized Light Application In Vivo

et al. 2023

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“…As shown in Figures 4A, B , the IC50 of the TMEscore-H group was not significantly different to that of the TMEscore-L group for cisplatin and docetaxel (P>0.05), but was significantly different for 5-fluorouracil, gemcitabine, and paclitaxel ( Figures 4C–E ). Furthermore, five chemotherapy drugs (temozolomide ( 24 ), pyrimethamine ( 25 ), lapatinib ( 26 ), doxorubicin ( 27 ), and ruxolitinib ( 28 )), which are reported to be associated with the treatment of CRC, showed significant differences between the TMEscore-H and TMEscore-L groups ( Figures 4F–J ). Thereafter, the expression levels of six known immune checkpoint inhibitors, namely PD1 (PDCD1), PD-L1, PD-L2 (PDCD1LG2), CD80, CD86, CTLA4, and CD274, were compared based on the TMEscore clusters.…”

Section: Resultsmentioning

confidence: 99%

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Guo

Lei

et al. 2022

Front. Oncol.

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BackgroundTumor-infiltrating immune cells (TIICs) are associated with chemotherapy response. This study aimed to explore the prognostic value of a TIIC-related tumor microenvironment score (TMEscore) in patients with colorectal cancer (CRC) who underwent chemotherapy and construct a TMEscore-related gene signature to determine its predictive value.MethodsGene profiles of patients who underwent fluoropyrimidine-based chemotherapy were collected, and their TIIC fractions were calculated and clustered. Differentially expressed genes (DEGs) between clusters were used to calculate the TMEscore. The association between the TMEscore, chemotherapy response, and survival rate was analyzed. Machine learning methods were used to identify key TMEscore-related genes, and a gene signature was constructed to verify the predictive value.ResultsTwo clusters based on the TIIC fraction were identified, and the TMEscore was calculated based on the DEGs of the two clusters. The TMEscore was higher in patients who responded to chemotherapy than in those who did not, and was associated with the survival rate of patients who underwent chemotherapy. Three machine learning methods, support vector machine (SVM), decision tree (DT), and Extreme Gradient Boosting (XGBoost), identified three TMEscore-related genes (ADH1C, SLC26A2, and NANS) associated with the response to chemotherapy. A TMEscore-related gene signature was constructed, and three external cohorts validated that the gene signature could predict the response to chemotherapy. Five datasets and clinical samples showed that the expression of the three TMEscore-related genes was increased in tumor tissues compared to those in control tissues.ConclusionsThe TIIC-based TMEscore was associated with the survival of CRC patients who underwent fluoropyrimidine-based chemotherapy, and predicted the response to chemotherapy. The TMEscore-related gene signature had a better predictive value for response to chemotherapy than for survival.

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“…Besides, 12 immunotherapy drugs about PDAC from GDSC websites were filtered, which paves the way for patients with PDAC in medical treatments. Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethylpyrimidine), a dihydrofolate reductase (DHFR) inhibitor, is used for treating malaria by inhibiting the proliferation of plasmodium and toxoplasma and also applied to anti-tumor field [ 36 ]. Furthermore, Phenformin, a common biguanide drug, can effectively treat diabetes.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel m6A-related lncRNAs signature and immunotherapeutic drug sensitivity in pancreatic adenocarcinoma

Li,

Yin,

Chen

et al. 2024

BMC Cancer

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Background Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related with poor prognosis and immunotherapeutic effect in PDAC. The aim of this study is to construct and validate a m6A-related lncRNAs signature and assess immunotherapeutic drug sensitivity in PDAC. Methods RNA-seq data for 178 cases of PDAC patients and 167 cases of normal pancreatic tissue were obtained from TCGA and GTEx databases, respectively. A set of 21 m6A-related genes were downloaded based on the previous report. Co-expression network was conducted to identify m6A-related lncRNAs in PDAC. Cox analyses and least absolute shrinkage and selection operator (Lasso) regression model were used to construct a risk prognosis model. The relationship between signature genes and immune function was explored by single-sample GSEA (ssGSEA). The tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB) were utilized to evaluate the response to immunotherapy. Furthermore, the expression levels of 4 m6A-related lncRNAs on PDAC cell lines were measured by the quantitative real-time PCR (qPCR). The drug sensitivity between the high- and low-risk groups was validated using PDAC cell lines by Cell-Counting Kit 8 (CCK8). Results The risk prognosis model was successfully constructed based on 4 m6A-related lncRNAs, and PDAC patients were divided into the high- and low-risk groups. The overall survival (OS) of the high-risk groups was more unfavorable compared with the low-risk groups. Receiver operating characteristic (ROC) curves demonstrated that the risk prognosis model reasonably predicted the 2-, 3- and 5-year OS of PDAC patients. qPCR analysis confirmed the decreased expression levels of 4 m6A-related lncRNAs in PDAC cells compared to the normal pancreatic cells. Furthermore, CCK8 assay revealed that Phenformin exhibited higher sensitivity in the high-risk groups, while Pyrimethamine exhibited higher sensitivity in the low-risk groups. Conclusion The prognosis of patients with PDAC were well predicted in the risk prognosis model based on m6A-related lncRNAs, and selected immunotherapy drugs have potential values for the treatment of pancreatic cancer.

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Pyrimethamine inhibits cell growth by inducing cell senescence and boosting CD8+ T-cell mediated cytotoxicity in colorectal cancer

Cited by 8 publications

References 39 publications

Melanoma Cell Reprogramming and Awakening of Antitumor Immunity as a Fingerprint of Hyper-Harmonized Hydroxylated Fullerene Water Complex (3HFWC) and Hyperpolarized Light Application In Vivo

Melanoma Cell Reprogramming and Awakening of Antitumor Immunity as a Fingerprint of Hyper-Harmonized Hydroxylated Fullerene Water Complex (3HFWC) and Hyperpolarized Light Application In Vivo

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Identification of a novel m6A-related lncRNAs signature and immunotherapeutic drug sensitivity in pancreatic adenocarcinoma

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