PKI-587 enhances radiosensitization of hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathways and DNA damage repair

Xie, Yan; Liu, Changwei; Zhang, Yinci; Li, Amin; Sun, Chong; Li, Rui; Xing, Yanwei; Shi, Minghong; Wang, Qi

doi:10.1371/journal.pone.0258817

Cited by 12 publications

(10 citation statements)

References 47 publications

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“…These compensatory mechanisms in tumor cells lead to different responses to treatment with DNA damage agents, as well as RT (1,48). Both RS and radiation activate a similar DDR pathway, providing the possibility of a synergistic effect of targeting RS with RT (49,50).…”

Section: Cell Cycle Distributionmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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Section: Cell Cycle Distributionmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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“…Activation of the PI3K/AKT pathway increases the expression of mTOR, which enters the nucleus and initiates the expression of CyclinD1, facilitating the rapid entry of cells into mitosis ( Xie et al, 2021 ). C-Myc stimulates cell cycle progression by regulating many genes related to cell cycle control ( Elbadawy et al, 2019 ; García-Gutiérrez et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Combining Network Pharmacology and Experimental Validation to Study the Action and Mechanism of Water extract of Asparagus Against Colorectal Cancer

Liang

Wang

et al. 2022

Front. Pharmacol.

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Asparagus (ASP) is a well-known traditional Chinese medicine with nourishing, moistening, fire-clearing, cough-suppressing, and intestinal effects. In addition, it exerts anti-inflammatory, antioxidant, anti-aging, immunity-enhancing, and anti-tumor pharmacological effect. The anti-tumor effect of ASP has been studied in hepatocellular carcinoma. However, its action and pharmacological mechanism in colorectal cancer (CRC) are unclear. The present study aimed to identify the potential targets of ASP for CRC treatment using network pharmacology and explore its possible therapeutic mechanisms using in vitro and in vivo experiments. The active compounds and potential targets of ASP were obtained from the TCMSP database, followed by CRC-related target genes identification using GeneCards and OMIM databases, which were matched with the potential targets of ASP. Based on the matching results, potential targets and signaling pathways were identified by protein-protein interaction (PPI), gene ontology (GO) functions, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Finally, in vitro and in vivo experiments were performed to further validate the anti-cancer effects of ASP on CRC. Network pharmacology analysis identified nine active components from ASP from the database based on oral bioavailability and drug similarity index, and 157 potential targets related to ASP were predicted. The PPI network identified tumor protein 53 (TP53), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), and AKT serine/threonine kinase 1 (AKT1) as key targets. GO analysis showed that ASP might act through response to wounding, membrane raft, and transcription factor binding. KEGG enrichment analysis revealed that ASP may affect CRC through the phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/AKT/mechanistic target of rapamycin kinase (mTOR) signaling pathway. In vitro, ASP inhibited cell proliferation, migration, and invasion of HCT116 and LOVO cells, and caused G0/G1 phase arrest and apoptosis in CRC cells. In vivo, ASP significantly inhibited the growth of CRC transplanted tumors in nude mice. Furthermore, pathway analysis confirmed that ASP could exert its therapeutic effects on CRC by regulating cell proliferation and survival through the PI3K/AKT/mTOR signaling pathway. This study is the first to report the potential role of ASP in the treatment of colorectal cancer.

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“…And AT-7529 could be also noticed as potential drugs for HER2-positive breast cancer ( Khanjani et al, 2021 ). PKI-587 enhanced chemosensitivity and radiosensitization of HCC by inhibiting PI3K/AKT/mTOR pathway ( Zhang et al, 2019 ; Xie et al, 2021 ). Moreover, PKI-587 demonstrated anti-tumor activity in ovarian cancer xenograft models ( Langdon et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Insights into the roles and driving forces of CCT3 in human tumors

Song²,

Liu³

et al. 2022

Front. Pharmacol.

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CCT3 played a key role in many cancers. This study aimed to further explore the characteristics of CCT3 from a pan-cancer perspective and reveal the driving forces for CCT3. By bioinformatic analysis, we found that the mRNA and protein levels of CCT3 were abnormally elevated in most tumor types and were correlated with poor prognosis. Single-cell sequencing data indicated an abnormal increase of CCT3 expression in both malignant cells and multiple immune cells. In the tumor microenvironment, CCT3 expression was negatively relevant with immune cell infiltration and immune checkpoint genes expression. In colon cancer, knockdown of CCT3 inhibited cell proliferation. Gene set enrichment analysis showed that CCT3 may be oncogenic by regulating amino acid metabolism. Furthermore, we predicted sensitive drugs for CCT3 by virtual screening and sensitivity analysis. Many driver genes such as TP53 and KRAS were essential for CCT3 overexpression. Epigenetic factors, enhancers in particular, were also critical for CCT3 expression. Additionally, we constructed the lncRNA/circRNA-miRNA-CCT3 regulatory network. Collectively, CCT3 had the potential to be a diagnostic and prognostic biomarker for multiple tumor types. CCT3 expression was relevant with an immunosuppressive tumor microenvironment. CCT3 could be a new molecular target for colon cancer. Both genetic and epigenetic factors were responsible for CCT3 expression in tumors.

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PKI-587 enhances radiosensitization of hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathways and DNA damage repair

Cited by 12 publications

References 47 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Combining Network Pharmacology and Experimental Validation to Study the Action and Mechanism of Water extract of Asparagus Against Colorectal Cancer

Insights into the roles and driving forces of CCT3 in human tumors

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