logo logo
Akt Pathway Inhibitors. Uko Nne E,Güner Osman F,Matesic Diane F,Bowen J Phillip Current topics in medicinal chemistry Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions. 10.2174/1568026620666200224101808
Novel association of oral squamous cell carcinoma with GSTP1 Arg187Trp gene polymorphism. Rajesh Deepa,Balakrishna Sharath,Azeem Mohiyuddin S M,Suryanarayana Ravishankar,Kutty A V Moideen Journal of cellular biochemistry AIMS:Glutathione S-transferase subtype pi 1 (GSTP1) is an enzyme that is involved in the detoxification of carcinogenic substances. Arg187Trp is a functional polymorphism in the corresponding GSTP1 gene that reduces the enzymatic activity by 45%. We evaluated, for the first time, the association of Arg187Trp with the risk of oral squamous cell carcinoma and compared it with other established GSTP1 polymorphisms viz, Ile105Val and Ala114Val. MATERIALS AND METHODS:We carried out a 1:2 case-control study by recruiting 100 patients with oral squamous cell carcinoma and 200 age and gender-matched healthy individuals. Ile105Val, Ala114Val, and Arg187Trp polymorphisms were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and their distribution in the study groups was compared by chi-squared test (Fisher's exact). RESULTS:The minor allele of Ala114Val and Arg187Trp were more common in patients than in controls. In contrast, the distribution of Ile105Val minor allele was similar in the two groups. The differential distribution was also significant at the level of genotypes. CONCLUSIONS:These results indicate that GSTP1 Arg187Trp is associated with the risk of developing oral squamous cell carcinoma. Our study underlines the importance of detoxification pathway in the risk of carcinogenesis. 10.1002/jcb.27877
Decreased expression of glutathione S-transferase pi correlates with poorly differentiated grade in patients with oral squamous cell carcinoma. Ma Hai-long,Yu Cong,Liu Ying,Tan Yi-ran,Qiao Jin-ke,Yang Xi,Wang Li-zhen,Li Jiang,Chen Qiong,Chen Fu-xiang,Zhang Zhi-yuan,Zhong Lai-ping Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology BACKGROUND:Glutathione S transferase pi (GSTP1) is a member of phase II detoxification enzymes as a major regulator of cell signaling in response to stress, hypoxia, growth factors, and other stimuli. The clinical role of GSTP1 in cancer is still unclear. The aim of this study was to investigate the serum GSTP1 level in patients with oral squamous cell carcinoma (OSCC) and the GSTP1 expression in tissue samples from patients with OSCC and OSCC lines. METHODS:One hundred and sixty-six patients with OSCC and 120 normal persons were used to screen potential serum peptide biomarkers using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Serum GSTP1 concentration was detected in 18 patients with OSCC and 18 normal persons using ELISA. Immunohistochemistry was used to detect GSTP1 expression in tissue samples from twenty-eight OSCC patients. Western blot and real-time PCR were used to detect GSTP1 expression in nine OSCC lines. RESULTS:Decreased GSTP1 concentration was found in the patients with OSCC compared with the normal persons by MALDI-TOF-MS, which was then confirmed by ELISA (P = 0.019). Decreased GSTP1 mRNA level and protein expression were also found in the OSCC lines. Decreased GSTP1 expression was found correlating with pathological differentiation grade in the tissue samples from OSCC patients, a lower GSTP1 expression indicating a poorer pathological differentiation grade (P = 0.041). CONCLUSIONS:These results suggest that decreased GSTP1 expression in patients with OSCC and a lower GSTP1 expression indicating a poorer pathological differentiation grade in OSCC tissue samples. 10.1111/jop.12229
GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation. Pincinato Eder C,Costa Ericka F D,Lopes-Aguiar Leisa,Nogueira Guilherme A S,Lima Tathiane R P,Visacri Marília B,Costa Anna P L,Lourenço Gustavo J,Calonga Luciane,Mariano Fernanda V,Altemani Albina M A M,Coutinho-Camillo Cláudia,Chone Carlos T,Ramos Celso D,Altemani João M C,Moriel Patrícia,Lima Carmen S P Scientific reports Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1, GSTT1and GSTP1, are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype (p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT. 10.1038/s41598-019-45808-6
Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review. Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology Background:Head and neck squamous cell carcinomas (HNSCCs) are associated with variable prognosis even with similar clinical characteristics and treatments. Gene polymorphisms have been suggested as prognostic factors for HNSCC which can justified this variable prognosis. So, the aim was to review literatures on gene polymorphisms and prognosis of HNSCCs. Materials and methods:A systematic search was conducted using PubMed, Web of science, SCOPUS, Google Scholar and Cochrane library databases to find all related articles published up to December 2021 in the field of gene polymorphisms and HNSCC prognosis. Results:Of 1029 initial searched articles, 71 articles were selected for inclusion in this systematic review. About 93 genes and 204 polymorphisms have been discussed in these articles. Among the most studied polymorphisms, the and polymorphisms were not associated with survival in most studies; the polymorphism had no significant association in any of the studies. Different gene polymorphisms of glutathione s-transferase family, including , and , were not associated with survival in included studies. There are conflicting results regarding the association between polymorphisms such as , , and with HNSCC prognosis. Less studied polymorphisms, such as or the , were generally not associated with HNSCC prognosis. Conclusion:Reviewed articles reported varied and contradictory results regarding the association of gene polymorphisms and HNSCC prognosis, which necessitates further studies along with meta-analysis on the results of such studies. 10.5603/RPOR.a2022.0109
GSTP1 c.341C>T gene polymorphism increases the risk of oral squamous cell carcinoma. Rajesh Deepa,Balakrishna Sharath,Azeem Mohiyuddin S M,Suresh T N,Moideen Kutty A V Mutation research. Genetic toxicology and environmental mutagenesis Glutathione S Transferases (GST) are anti-oxidant enzymes involved in detoxification of cellular and exogenous carcinogens and oxidative products of reactive oxygen species. Genetic polymorphisms can attenuate the detoxification capacity of GST and consequently increase the susceptibility to carcinogenesis. There are eight classes of GST enzymes of which pi subtype is the predominant form expressed in the oral mucosa. c.341C > T single nucleotide polymorphism (rs1138272) in GSTP1 gene, is a functional variation that reduces the enzymatic activity of GST pi. We carried out a 1:2 case-control study involving 270 individuals to determine the association of c.341C > T variation with the risk of oral squamous cell carcinoma. GSTP1 c.341C > T variation was genotyped by PCR-RFLP method. GST pi expression in the tumour sample was determined by immunohistochemistry. Tobacco consumption was the major risk factor among cancer patients. The odds ratio for the risk of oral squamous cell carcinoma in individuals with the minor allele was 4.5 (0.95 CI = 2.3-8.9; P = 0.000004). The genotype was found to follow dominant mode of inheritance (OR 4.4 [0.95 CI = 2.1-9.2]; P = 0.00006). Our results support the conclusion that c.341C > T variation in GSTP1 increases the risk of OSCC in patients habituated to tobacco consumption. 10.1016/j.mrgentox.2018.04.006
Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Glutathione S-transferase pi (GSTP1), a phase II detoxification enzyme, is known to be overexpressed and mediates chemotherapeutic resistance in lung cancer. However, whether GSTP1 supports cancer stem cells (CSCs) and the underlying mechanisms in lung adenocarcinoma (LUAD) remain largely unknown. This study unveiled that GSTP1 is upregulated in lung CSCs and supports tumor self-renewal, metastasis, and resistance to targeted tyrosine kinase inhibitors of LUAD both in vitro and in vivo. Mechanistically, CaMK2A (calcium/calmodulin-dependent protein kinase 2 isoform A)/NRF2 (nuclear factor erythroid 2-related factor 2)/GSTP1 is uncovered as a regulatory axis under hypoxia. CaMK2A increased GSTP1 expression through phosphorylating the Sersine558 residue of NRF2 and promoting its nuclear translocation, a novel mechanism for NRF2 activation apart from conventional oxidization-dependent activation. Upregulation of GSTP1 in turn suppressed reactive oxygen species levels and supported CSC phenotypes. Clinically, GSTP1 analyzed by immunohistochemistry is upregulated in a proportion of LUAD and serves as a prognostic marker for survival. Using patient-derived organoids from an ALK-translocated LUAD, the therapeutic potential of a specific GSTP1 inhibitor ezatiostat in combination treatment with the ALK inhibitor crizotinib is demonstrated. This study demonstrates GSTP1 to be a promising therapeutic target for long-term control of LUAD through targeting CSCs. 10.1002/advs.202205262
GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer. Nakayama Masashi,Gonzalgo Mark L,Yegnasubramanian Srinivasan,Lin Xiaohui,De Marzo Angelo M,Nelson William G Journal of cellular biochemistry Somatic hypermethylation of CpG island sequences at GSTP1, the gene encoding the pi-class glutathione S-transferase, appears to be characteristic of human prostatic carcinogenesis. To consider the potential utility of this epigenetic alteration as a biomarker for prostate cancer, we present here a comprehensive review of the literature describing somatic GSTP1 changes in DNA from prostate cells and tissues. GSTP1 CpG island hypermethylation has been detected in prostate cancer DNA using a variety of assay techniques, including (i) Southern blot analysis (SB), after treatment with (5-m)C-sensitive restriction endonucleases, (ii) the polymerase chain reaction, following treatment with (5-m)C-sensitive restriction endonucleases (RE-PCR), (iii) bisulfite genomic sequencing (BGS), and (iv) bisulfite modification followed by the polymerase chain reaction, using primers selective for target sequences containing (5-m)C (MSP). In the majority of the case series so far reported, GSTP1 CpG island hypermethylation was present in DNA from at least 90% of prostate cancer cases. When analyses have been carefully conducted, GSTP1 CpG island hypermethylation has not been found in DNA from normal prostate tissues, or from benign prostatic hyperplasia (BPH) tissues, though GSTP1 CpG island hypermethylation changes have been detected in DNA from candidate prostate cancer precursor lesions proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN). Using PCR methods, GSTP1 CpG island hypermethylation has also been detected in urine, ejaculate, and plasma from men with prostate cancer. GSTP1 CpG island hypermethylation, a somatic epigenetic alteration, appears poised to serve as a molecular biomarker useful for prostate cancer screening, detection, and diagnosis. 10.1002/jcb.10740
Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis. Li Yang,Cai Yihong,Chen He,Mao Leijin Journal of cancer research and therapeutics OBJECTIVE:To quantitatively investigate the effect of GSTP1 hypermethylation on hepatocellular carcinoma (HCC) using a meta-analysis of available case-control studies. MATERIALS AND METHODS:Previous studies have primarily evaluated the incidence of GSTP1 hypermethylation in HCC and corresponding control groups, and compared the incidence of GSTP1 hypermethylation in tumor tissues, pericancer liver tissues, normal liver issues, and nontumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of GSTP1 hypermethylation in both groups were collected from these studies and summarized. Eleven studies, including 546 cases of HCC and 575 nontumor cases, were identified for meta-analysis. RESULTS:Statistically significant odds ratios (ORs) of GSTP1 hypermethylation were obtained from tumor tissues and nontumorous liver tissues of HCC patients (OR 2.63, 95% confidence interval [CI]: 1.77-3.89%, P < 0.0001), tumor tissues of HCC patients, healthy liver tissues of patients with other diseases (OR 7.29, 95% CI: 2.87-18.51%, P < 0.0001), tumor tissues of HCC patients, and liver tissues of patients with nontumorous liver diseases (OR 2.13, 95% CI: 1.10-4.13%, P < 0.05). The pooled analysis showed significantly increased ORs of GSTP1 hypermethylation (OR 2.21, 95% CI: 1.01-4.84%, P < 0.05) from HCC tissues and cirrhotic tissues. CONCLUSIONS:The results of this meta-analysis suggest that GSTP1 hypermethylation induces the inactivation of GSTP1 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC. 10.4103/0973-1482.181179
GSTP1 methylation in cancer: a liquid biopsy biomarker? Gurioli Giorgia,Martignano Filippo,Salvi Samanta,Costantini Matteo,Gunelli Roberta,Casadio Valentina Clinical chemistry and laboratory medicine The coding region of GSTP1 gene is preceded by a large CpG-rich region that is frequently affected by methylation. In many cancer types, GSTP1 is affected by hypermethylation and, as a consequence, it has a low expression. The aim of this review is to give an overview on GSTP1 methylation studies with a special focus on liquid biopsy, thus to summarize methods, results, sample types, different diseases, to have a complete information regarding this promising epigenetic biomarker. We used all the most valuable scientific search engines (PubMed, Medline, Scopus and Web of Science) searching the following keywords: GSTP1, methylation, cancer, urine, serum, plasma and blood. GSTP1 is a largely investigated tissue biomarker in several malignancies such as prostate, breast, lung and hepatocellular carcinoma with good performances especially for diagnostic purposes. As a liquid biopsy biomarker, it has been mainly investigated in prostate cancer (PCa) where it showed a high specificity but a low sensitivity; thus, it is recommended in combination with other biomarkers. Despite the large number of published papers and the promising results, GSTP1 has not yet entered the clinical practice even for PCa diagnosis. For this reason, further large and prospective studies are needed to validate this assay. 10.1515/cclm-2017-0703
GSTP1 and cancer: Expression, methylation, polymorphisms and signaling (Review). Cui Jian,Li Guoqing,Yin Jie,Li Linwei,Tan Yue,Wei Haoran,Liu Bang,Deng Lihong,Tang Jialu,Chen Yonglin,Yi Lan International journal of oncology Glutathione S‑transferase Pi (GSTP1) is an isozyme encoded by the GST pi gene that plays an important regulatory role in detoxification, anti‑oxidative damage, and the occurrence of various diseases. The aim of the present study was to review the association between the expression of GSTP1 and the development and treatment of various cancers, and discuss GSTP1 methylation in several malignant tumors, such as prostate, breast and lung cancer, as well as hepatocellular carcinoma; to review the association between polymorphism of the GSTP1 gene and various diseases; and to review the effects of GSTP1 on electrophilic oxidative stress, cell signal transduction, and the regulation of carcinogenic factors. Collectively, GSTP1 plays a major role in the development of various diseases. 10.3892/ijo.2020.4979
SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation. Molecular cell Ferroptosis is a non-apoptotic form of regulated cell death. Glutathione (GSH) peroxidase 4 (GPX4) and GSH-independent ferroptosis suppressor protein 1 (FSP1) have been identified as major defenses. Here, we uncover a protective mechanism mediated by GSH S-transferase P1 (GSTP1) by monitoring proteinomic dynamics during ferroptosis. Dramatic downregulation of GSTP1 is caused by SMURF2-mediated GSTP1 ubiquitination and degradation at early stages of ferroptosis. Intriguingly, GSTP1 acts in GPX4- and FSP1-independent manners by catalyzing GSH conjugation of 4-hydroxynonenal and detoxifying lipid hydroperoxides via selenium-independent GSH peroxidase activity. Genetic modulation of the SMURF2/GSTP1 axis or the pharmacological inhibition of GSTP1's catalytic activity sensitized tumor responses to Food and Drug Administration (FDA)-approved ferroptosis-inducing drugs both in vitro and in vivo. GSTP1 expression also confers resistance to immune checkpoint inhibitors by blunting ferroptosis. Collectively, these findings demonstrate a GPX4/FSP1-independent cellular defense mechanism against ferroptosis and suggest that targeting SMURF2/GSTP1 to sensitize cancer cells to ferroptosis has potential as an anticancer therapy. 10.1016/j.molcel.2023.10.042