Cancer Informatics最新文献

{"title":"An In Silico Analysis Reveals an EMT-Associated Gene Signature for Predicting Recurrence of Early-Stage Lung Adenocarcinoma","authors":"Yi Han, F. Wong, Di Wang, C. Kahlert","doi":"10.1177/11769351221100727","DOIUrl":"https://doi.org/10.1177/11769351221100727","url":null,"abstract":"Background: The potential micrometastasis tends to cause recurrence of lung adenocarcinoma (LUAD) after surgical resection and consequently leads to an increase in the mortality risk. Compelling evidence has suggested the underlying mechanisms of tumor metastasis could involve the activation of an epithelial-mesenchymal transition (EMT) program. Hence, the objective of this study was to develop an EMT-associated gene signature for predicting the recurrence of early-stage LUAD. Methods: The mRNA expression data of patients with early-stage LUAD were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) available databases. Gene Set Variation Analysis (GSVA) was first performed to provide an assessment of EMT phenotype, whereas Weighted Gene Co-expression Network Analysis (WGCNA) was constructed to determine EMT-associated key modules and genes. Based on the genes, a novel EMT-associated signature for predicting the recurrence of early-stage LUAD was identified using a least absolute shrinkage and selection operator (LASSO) algorithm and a stepwise Cox proportional hazards regression model. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves and Cox regression analyses were used to estimate the performance of the identified gene signature. Results: GSVA revealed diverse EMT states in the early-stage LUAD. Further correlation analyses showed that the EMT states presented high correlations with several hallmarks of cancers, tumor purity, tumor microenvironment cells, and immune checkpoint genes. More importantly, Kaplan-Meier survival analyses indicated that patients with high EMT scores had worse recurrence-free survival (RFS) and overall survival (OS) than those with low EMT scores. A novel 5-gene signature (AGL, ECM1, ENPP1, SNX7, and TSPAN12) was established based on the EMT-associated genes from WGCNA and this signature successfully predicted that the high-risk patients had a higher recurrence rate compared with the low-risk patients. In further analyses, the signature represented robust prognostic values in 2 independent validation cohorts (GEO and TCGA datasets) and a combined GEO cohort as evaluated by Kaplan-Meier survival (P-value < .0001) and ROC analysis (AUC = 0.781). Moreover, the signature was corroborated to be independent of clinical factors by univariate and multivariate Cox regression analyses. Interestingly, the combination of the signature-based recurrence risk and tumor-node-metastasis (TNM) stage showed a superior predictive ability on the recurrence of patients with early-stage LUAD. Conclusion: Our study suggests that patients with early-stage LUAD exhibit diverse EMT states that play a vital role in tumor recurrence. The novel and promising EMT-associated 5-gene signature identified and validated in this study may be applied to predict the recurrence of early-stage LUAD, facilitating risk stratification, recurrence monitoring, and individualized management for the patient","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49035005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Increased Prevalence of TP53 Mutations in Metastatic Prostate Cancer","authors":"Wensheng Zhang, Yan Dong, O. Sartor, Kun Zhang","doi":"10.1177/11769351221087046","DOIUrl":"https://doi.org/10.1177/11769351221087046","url":null,"abstract":"The prevalence of TP53 mutations in advanced prostate cancers (PCa) is 3 to 5 times of the quantity in primary PCa. By an integrative analysis of the Cancer Genome Atlas and Catalogue of Somatic Mutations in Cancer data, we revealed the supporting evidence for 2 complementary hypotheses: H1 - TP53 abnormalities promote metastasis or therapy-resistance of PCa cells, and H2—part of TP53 mutations in PCa metastases occur after the diagnosis of original cancers. The plausibility of these hypotheses can explain the increased prevalence of TP53 mutations in PCa metastases. With H1 and H2 as the general assumptions, we developed mathematical models to decipher the change of the percentage frequency (prevalence) of TP53 mutations from primary tumors to metastases. The following results were obtained. Compared to TP53-normal patients, TP53-mutated patients had poorer biochemical relapse-free survival, higher Gleason scores, and more advanced t-stages (P < .01). Single-nucleotide variants in metastases more frequently occurred on G bases of the coding sequence than those in primary cancers (P = .03). The profile of TP53 hotspot mutations was significantly different between primary and metastatic PCa as demonstrated in a set of statistical tests (P < .05). By the derived formulae, we estimated that about 40% TP53 mutation records collected from metastases occurred after the diagnosis of the original cancers. Our study provided significant insight into PCa progression. The proposed models can also be applied to decipher the prevalence of mutations on TP53 (or other driver genes) in other cancer types.","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"21 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42356781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Transcriptome Analysis Reveals Paraspeckles Expression in Osteosarcoma Tissues.","authors":"Emel Rothzerg,&nbsp;Wenyu Feng,&nbsp;Dezhi Song,&nbsp;Hengyuan Li,&nbsp;Qingjun Wei,&nbsp;Archa Fox,&nbsp;David Wood,&nbsp;Jiake Xu,&nbsp;Yun Liu","doi":"10.1177/11769351221140101","DOIUrl":"https://doi.org/10.1177/11769351221140101","url":null,"abstract":"<p><p>Nuclear paraspeckles are subnuclear bodies contracted by nuclear-enriched abundant transcript 1 (NEAT1) long non-coding RNA, localised in the interchromatin space of mammalian cell nuclei. Paraspeckles have been critically involved in tumour progression, metastasis and chemoresistance. To this date, there are limited findings to suggest that paraspeckles, NEAT1 and heterogeneous nuclear ribonucleoproteins (hnRNPs) directly or indirectly play roles in osteosarcoma progression. Herein, we analysed NEAT1, paraspeckle proteins (SFPQ, PSPC1 and NONO) and hnRNP members (HNRNPK, HNRNPM, HNRNPR and HNRNPD) gene expression in 6 osteosarcoma tumour tissues using the single-cell RNA-sequencing method. The normalised data highlighted that the paraspeckles transcripts were highly abundant in osteoblastic OS cells, except NEAT1, which was highly expressed in myeloid cell 1 and 2 subpopulations.</p>","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"21 ","pages":"11769351221140101"},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4d/17/10.1177_11769351221140101.PMC9730017.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10333451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowledge, Attitude, and Practice Toward Cervical Cancer Screening and Associated Factors Among College and University Female Students in Dire Dawa City, Eastern Ethiopia","authors":"H. Bekele, A. Nuri, Legesse Abera","doi":"10.1177/11769351221084808","DOIUrl":"https://doi.org/10.1177/11769351221084808","url":null,"abstract":"Introduction: Cervical cancer is preventable and, in most cases, curable if identified at an early stage. Cervical cancer is the second leading cause of cancer-related mortality Ethiopia with screening accounting for only 0.8%. Furthermore, female students and young adults in colleges and universities’ have a high prevalence of genital HPV infection because of their risky sexual behavior, lack of knowledge on screening and very few students receive screening services. This study aimed to assess the Knowledge, attitudes, and practice toward cervical cancer screening and its associated factors among female college students in Dire Dawa City, Ethiopia. Methods: An institutional-based cross-sectional study was conducted using a multistage sampling technique from November to December 2020, among 730 female college students in Dire Dawa. Descriptive statistics and binary logistic regression were used to describe each variable and identify associations between the dependent and independent variables respectively. Adjusted odds ratio with 95% confidence interval and P-value <.05 used to determine the association. Results: The results showed, only 64 (9.3%) participants were knowledgeable, 413 (60.1%) had positive attitudes and 17 (2.5%) were screened in their lifetime. Age group, years of study, and history of cervical cancer practice were significantly associated with knowledge of cervical cancer screening. The year of study was based on cervical cancer smears and the number of screenings was significantly associated with attitude. Conclusion: This study showed that students’ knowledge of cervical cancer screening is low. Overall attitudes toward cervical cancer screening among female students were good, but only a small proportion of students had undergone cervical cancer screening. The most common reasons for the low screening practice were lack of information and undecided. There is a need to promote different campaigns for cervical cancer screening programs, in order to increase awareness.","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44368152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico Prediction on the PI3K/AKT/mTOR Pathway of the Antiproliferative Effect of O. joconostle in Breast Cancer Models","authors":"Alejandra Ortiz-González, P. P. González-Pérez, M. Cárdenas-García, M. Hernández-Linares","doi":"10.1177/11769351221087028","DOIUrl":"https://doi.org/10.1177/11769351221087028","url":null,"abstract":"The search for new cancer treatments from traditional medicine involves developing studies to understand at the molecular level different cell signaling pathways involved in cancer development. In this work, we present a model of the PI3K/Akt/mTOR pathway, which plays a key role in cell cycle regulation and is related to cell survival, proliferation, and growth in cancer, as well as resistance to antitumor therapies, so finding drugs that act on this pathway is ideal to propose a new adjuvant treatment. The aim of this work was to model, simulate and predict in silico using the Big Data-Cellulat platform the possible targets in the PI3K/Akt/mTOR pathway on which the Opuntia joconostle extract acts, as well as to indicate the concentration range to be used to find the mean lethal dose in in vitro experiments on breast cancer cells. The in silico results show that, in a cancer cell, the activation of JAK and STAT, as well as PI3K and Akt is related to the effect of cell proliferation, angiogenesis, and inhibition of apoptosis, and that the extract of O. joconostle has an antiproliferative effect on breast cancer cells by inhibiting cell proliferation, regulating the cell cycle and inhibiting apoptosis through this signaling pathway. In vitro it was demonstrated that the extract shows an antiproliferative effect, causing the arrest of cells in the G2/M phase of the cell cycle. Therefore, it is concluded that the use of in silico tools is a valuable method to perform virtual experiments and discover new treatments. The use of this type of model supports in vitro experimentation, reducing the costs and number of experiments in the real laboratory.","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42815755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Clinical Decision Support System for Increasing Compliance with Protocols in Chemotherapy of Children with Acute Lymphoblastic Leukemia","authors":"H. Moghaddasi, Rezvan Rahimi, Alireza Kazemi, Khadijeh Arjmandi Rafsanjani, G. Bahoush, Forough Rahimi","doi":"10.1177/11769351221084812","DOIUrl":"https://doi.org/10.1177/11769351221084812","url":null,"abstract":"Objective: In this survey, a protocol-based Chemotherapy Prescription Decision Support System (CPDSS) was designed and evaluated to reduce medication errors in the chemotherapy process of children with ALL. Methods: The CPDSS algorithm was extracted by the software development team based on the protocol used by doctors to treat children with ALL. The ASP.Net MVC and SQL Server 2016 programming languages were used to develop the system. A 3-step evaluation (technical, retrospective, and user satisfaction) was performed on CPDSS designed at 2 children’s hospitals in Tehran. The data were analyzed using descriptive statistics. At the technical evaluation step, users provided recommendations included in the system. Results: In the retrospective CPDSS evaluation step, 1281 prescribed doses of the drugs related to 30 patients were entered into the system. CPDSS detected 735 cases of protocol deviations and 57 (95%, CI = 1.25-2.55) errors in prescribed chemotherapy for children with ALL. In the user satisfaction evaluation, the users approved two dimensions of the user interface and functionality of the system. Conclusions: With the provision of alerts, the CPDSS can help increase compliance with chemotherapy protocols and decrease the chemotherapy prescribing errors that can improve patient safety.","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42461319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying the Therapeutic and Prognostic Role of the CD8+ T Cell-Related Gene ALDH2 in Head and Neck Squamous Cell Carcinoma.","authors":"Hongmei Zhang,&nbsp;Zhaozheng Li,&nbsp;Yan Zheng","doi":"10.1177/11769351221139252","DOIUrl":"https://doi.org/10.1177/11769351221139252","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSC) is a widely known malignancy which is usually diagnosed late and has a poor prognosis. This study focuses on finding a new gene linked with CD8+ <i>T</i> cell infiltration as a prognostic marker for patients with HNSC. Differential analysis of transcriptomic data was performed between HNSC and control tissues from TCGA and GEO database. The CD8+ <i>T</i> cell infiltration score was quantified using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) algorithms were used to identify key modules associated with CD8+ <i>T</i> cell infiltration. Kaplan-Meier (K-M) survival analysis was used to compare overall survival (OS) between the 2 groups. Univariate and multivariate Cox analyses were used to assess independent prognostic markers. The results showed CD8+ <i>T</i> cell infiltration score was an independent favorable prognostic marker in HNSC. Differential analysis and WGCNA identified 93 differential gene related to high CD8+ <i>T</i> infiltration. Amog the 93 genes, ALDH2 was an independent favorable prognostic marker in HNSC. ALDH2 expression was found to be much lower in HNSC, and patients with low ALDH2 expression had higher T stage and N stage. The correlation analysis showed that ALDH2 was linked with immune cell infiltration in the tumor microenvironment of HNSC. Patients having increased expression of ALDH2 tend to be sensitive to immune checkpoint inhibitors (ICIs). In addition, we showed the relationship between ALDH2 expression and chemotherapeutic drug sensitivity. In conclusion, this study identified ALDH2 as a prognostic marker, associated with CD8+ <i>T</i> cell infiltration in HNSC.</p>","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"21 ","pages":"11769351221139252"},"PeriodicalIF":2.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0b/19/10.1177_11769351221139252.PMC9772952.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10440113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prognostic Significance of Proteasome 26S Subunit, Non-ATPase (PSMD) Genes for Bladder Urothelial Carcinoma Patients.","authors":"AbdulFattah Salah Fararjeh,&nbsp;Ali Al-Khader,&nbsp;Malak Al-Saleem,&nbsp;Rinad Abu Qauod","doi":"10.1177/11769351211067692","DOIUrl":"https://doi.org/10.1177/11769351211067692","url":null,"abstract":"<p><p>Proteasome a highly sophisticated systems that alter protein structure and function. Proteasome 26S Subunit, Non-ATPase (PSMD) genes have been implicated in several types of malignancies. This is the first study to look at how proteasomal subunits are expressed in patients with bladder urothelial carcinoma (BLCA). BLCA was used to evaluate the predictive value of PSMD genes (PSMD1 to PSMD12) in relation to clinicopathological characteristics. PSMD genes' expression patterns at the mRNA level were analyzed using a variety of bioinformatics methods, including gene expression profile integrative analysis (GEPIA), Oncomine, TCGA, and Gene expression Omnibus (GEO) databases. The GEPIA and TCGA dataset survival plot functions were used to assess the prognostic significance of PSMD genes. PSMD2, PSMD3, PSMD4, PSMD8, and PSMD11 genes were significantly overexpressed in BLCA compared with normal bladder tissues. PSMD2 and PSMD8 were significantly overexpressed in BLCA more than other types of cancer. High level of PSMD2 and PSMD8 predicted shorter overall (OS) and progression free survival (PFS) in BLCA patients. High level of PSMD2 was significantly associated with elder age (<i>P</i> <i><</i> .001), female gender (<i>P</i> = .014), tumor grade (<i>P</i> <i><</i> .001), and metastasis (<i>P</i> = .003). PSMD2 has been shown to be an independent predictor for OS in BLCA patients based on univariate and multivariate analysis (<i>P</i> <i><</i> .001). Overall, according to this study, PSMD2 and PSMD8 could be served as a prognostic biomarker for BLCA patients.</p>","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"20 ","pages":"11769351211067692"},"PeriodicalIF":2.0,"publicationDate":"2021-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/54/10.1177_11769351211067692.PMC8725213.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39791623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Cervical Cancer and Associated Factors Among Women Attended Cervical Cancer Screening Center at Gahandi Memorial Hospital, Ethiopia.","authors":"Mulugeta Mekuria,&nbsp;Kebede Edosa,&nbsp;Mulualem Endashaw,&nbsp;Elias Teferi Bala,&nbsp;Eshetu E Chaka,&nbsp;Berhanu Senbeta Deriba,&nbsp;Bikila Tesfa","doi":"10.1177/11769351211068431","DOIUrl":"https://doi.org/10.1177/11769351211068431","url":null,"abstract":"<p><strong>Background: </strong>Despite the fact that cervical cancer is preventable disease, it is the fourth most frequently diagnosed cancer and leading cause of cancer death in women. An estimated 604 000 women were diagnosed with cervical cancer worldwide and 342 000 women died from the disease. Therefore, the purpose of this study was to determine the prevalence and factors associated with cervical cancer among women attended cervical cancer screening center in Gahandi memorial Hospital.</p><p><strong>Methods: </strong>An institutional-based cross-sectional study was conducted at Gahandi Memorial Hospital in which simple random sampling technique was used to select 422 registration books of women who visited the hospital between May 2015 and May 2019. Texts, tables, and graph were used to present results. Binary logistic regression with a <i>P</i>-value of <.25 and multivariate logistic regression with a <i>P</i>-value of <.05 were used to determine the association between independent variables and outcome variable.</p><p><strong>Results: </strong>In this study, from the total of 422 women screened with visual inspection with acetic acid (VIA) screening test, 23.5% of them were found to be positive for VIA test. From those who were diagnosed positive with VIA screening test, about 10.1 % were identified with high grade lesions. Having multiple sexual partners (AOR = 1.83, 95% CI: 1.21-3.29), being HIV-positive (AOR = 2.22, 95% CI:1.10-4.69), having a history of Sexual Transmitted Infection (STI) (AOR = 6.76, 95% CI: 1.14-3.90), and beginning sexual intercourse at early age (AOR = 1.38, 95% CI: 1.20-5.13) were factors associated with cervical cancer.</p><p><strong>Conclusion: </strong>The study concluded that the high prevalence of cervical cancer. Having multiple sexual partners, being Human Immune Deficiency Virus (HIV) positive, having STI history and early initiation of sexual intercourse were factors associated with cervical cancer. Therefore, avoiding multiple sexual partners, delaying of early sexual contact, and self-protection from STI infections might help to prevent cervical cancer.</p>","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"20 ","pages":"11769351211068431"},"PeriodicalIF":2.0,"publicationDate":"2021-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d2/3e/10.1177_11769351211068431.PMC8725021.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39791625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil.","authors":"Jonathan Mitchel,&nbsp;Pratima Bajaj,&nbsp;Ketki Patil,&nbsp;Austin Gunnarson,&nbsp;Emilie Pourchet,&nbsp;Yoo Na Kim,&nbsp;Jeffrey Skolnick,&nbsp;S Balakrishna Pai","doi":"10.1177/11769351211065979","DOIUrl":"https://doi.org/10.1177/11769351211065979","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer is the third largest cause of cancer-related mortality worldwide. Although current treatments with chemotherapeutics have allowed for management of colorectal cancer, additional novel treatments are essential. Intervening with the metabolic reprogramming observed in cancers called \"Warburg Effect,\" is one of the novel strategies considered to combat cancers. In the metabolic reprogramming pathway, pyruvate dehydrogenase kinase (PDK1) plays a pivotal role. Identification and characterization of a PDK1 inhibitor is of paramount importance. Further, for efficacious treatment of colorectal cancers, combinatorial regimens are essential. To this end, we opted to identify a PDK1 inhibitor using computational structure-based drug design FINDSITE^comb and perform combinatorial studies with 5-FU for efficacious treatment of colorectal cancers.</p><p><strong>Methods: </strong>Using computational structure-based drug design FINDSITE^comb, stearic acid (SA) was identified as a possible PDK1 inhibitor. Elucidation of the mechanism of action of SA was performed using flow cytometry, clonogenic assays.</p><p><strong>Results: </strong>When the growth inhibitory potential of SA was tested on colorectal adenocarcinoma (DLD-1) cells, a 50% inhibitory concentration (IC₅₀) of 60 µM was recorded. Moreover, SA inhibited the proliferation potential of DLD-1 cells as shown by the clonogenic assay and there was a sustained response even after withdrawal of the compound. Elucidation of the mechanism of action revealed, that the inhibitory effect of SA was through the programmed cell death pathway. There was increase in the number of apoptotic and multicaspase positive cells. SA also impacted the levels of the cell survival protein Bcl-2. With the aim of achieving improved treatment for colorectal cancer, we opted to combine 5-fluorouracil (5-FU), the currently used drug in the clinic, with SA. Combining SA with 5-FU, revealed a synergistic effect in which the IC₅₀ of 5-FU decreased from 25 to 6 µM upon combination with 60 µM SA. Further, SA did not inhibit non-tumorigenic NIH-3T3 proliferation.</p><p><strong>Conclusions: </strong>We envision that this significant decrease in the IC₅₀ of 5-FU could translate into less side effects of 5-FU and increase the efficacy of the treatment due to the multifaceted action of SA. The data generated from the current studies on the inhibition of colorectal adenocarcinoma by SA discovered by the use of the computational program as well as synergistic action with 5-FU should open up novel therapeutic options for the management of colorectal adenocarcinomas.</p>","PeriodicalId":35418,"journal":{"name":"Cancer Informatics","volume":"20 ","pages":"11769351211065979"},"PeriodicalIF":2.0,"publicationDate":"2021-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f0/cb/10.1177_11769351211065979.PMC8679029.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39738465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}