Antiproliferative activity of (R)-4′-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition

et al. 2020

Cancer Cell Int

Background: Activation of nuclear factor-kappa B (NF-κΒ) through DNA damage is one of the causes of tumor cell resistance to radiotherapy. Chromosome region 1 (CRM1) regulates tumor cell proliferation, drug resistance, and radiation resistance by regulating the nuclear-cytoplasmic translocation of important tumor suppressor proteins or protooncoproteins. A large number of studies have reported that inhibition of CRM1 suppresses the activation of NF-κΒ. Thus, we hypothesize that the reversible CRM1 inhibitor S109 may induce radiosensitivity in glioblastoma (GBM) by regulating the NF-κΒ signaling pathway. Methods: This study utilized the cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and colony formation assay to evaluate the effect of S109 combined with radiotherapy on the proliferation and survival of GBM cells. The therapeutic efficacy of S109 combined with radiotherapy was evaluated in vivo to explore the therapeutic mechanism of S109-induced GBM radiosensitization. Results: We found that S109 combined with radiotherapy significantly inhibited GBM cell proliferation and colony formation. By regulating the levels of multiple cell cycle-and apoptosis-related proteins, the combination therapy induced G1 cell cycle arrest in GBM cells. In vivo studies showed that S109 combined with radiotherapy significantly inhibited the growth of intracranial GBM and prolonged survival. Importantly, we found that S109 combined with radiotherapy promoted the nuclear accumulation of IκΒα, and inhibited phosphorylation of p65 and the transcriptional activation of NF-κΒ. Conclusion: Our findings provide a new therapeutic regimen for improving GBM radiosensitivity as well as a scientific basis for further clinical trials to evaluate this combination therapy.

mentioning

confidence: 99%

RETRACTED ARTICLE: Reversible inhibitor of CRM1 sensitizes glioblastoma cells to radiation by blocking the NF-κB signaling pathway

Liu

et al. 2020

Cancer Cell Int

“…Chen et al demonstrated that EpCAM + –CD133 + HCC cells better represent the LCSCs than the CD133 + –EpCAM − , CD133 − –EpCAM + and CD133 − –EpCAM − HCC cells 23 . The combination of EpCAM + –CD133 + as LCSC markers was also successfully employed in the isolation and identification of LCSCs by a number of other laboratories 26 , 52 , 53 . Therefore, we adopted the expression of EpCAM and CD133 as a phenotypical marker to define the LCSC population in this study.…”

Section: Discussionmentioning

confidence: 99%

The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells

Xiang

et al. 2021

Sci Rep

Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.

“…Another novel N-(3-(phenoxy methyl) phenyl) acetamide derivative also inhibits NSCLC cell proliferation by selectively inhibiting SIRT-2 [ 131 ]. (R) -40-methylKlavuzon and its derivative TK126 have cytotoxic effects on cancer stem cells in the huh-7 hepatocellular carcinoma cell line and showed more effective extracellular toxicity compared with sorafenib and regorafenib, possibly due to inhibition of SIRT-1/HDAC and CRM1 activity leading to cell cycle block [ 132 ]. The selective SIRT-6 activator 2- (1-benzofuran-2-yl) -N- (diphenylmethyl) quinoline-4-formamide (12Q) is also a promising lead compound for the treatment of pancreatic ductal adenocarcinoma [ 133 ].…”

Section: Nad Pathway-related Tumor Therapymentioning

confidence: 99%

Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment

Liu

Mohseni

et al. 2022

Cancer Cell Int

Nicotinamide adenine dinucleotide (NAD) is the core of cellular energy metabolism. NAMPT, Sirtuins, PARP, CD38, and other molecules in this classic metabolic pathway affect many key cellular functions and are closely related to the occurrence and development of many diseases. In recent years, several studies have found that these molecules can regulate cell energy metabolism, promote the release of related cytokines, induce the expression of neoantigens, change the tumor immune microenvironment (TIME), and then play an anticancer role. Drugs targeting these molecules are under development or approved for clinical use. Although there are some side effects and drug resistance, the discovery of novel drugs, the development of combination therapies, and the application of new technologies provide solutions to these challenges and improve efficacy. This review presents the mechanisms of action of NAD pathway-related molecules in tumor immunity, advances in drug research, combination therapies, and some new technology-related therapies.