• Biomedical Science Letters
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• v.29 no.3
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• pp.178-183
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• 2023

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. Regulation of the cytotoxic activity of NK cells relies on integrated interactions between inhibitory receptors and numerous activating receptors that act in tandem to eliminate tumor cells efficiently. Conventional chemotherapy is designed to produce an anti-proliferative or cytotoxic effect on early tumor cell division. Therapies designed to kill cancer cells and simultaneously maintain host anti-tumor immunity are attractive strategies for controlling tumor growth. Depending on the drug and dose used, several chemotherapeutic agents cause DNA damage and cancer cell death through apoptosis, immunogenic cell death, or other forms of non-killing (i.e., mitotic catastrophe, senescence, autophagy). Among stress-induced immunostimulatory proteins, changes in the expression levels of NK cell activating and inhibitory ligands and tumor cell death receptors play an important role in the detection and elimination by innate immune effectors including NK cells. Therefore, we will address how these cytotoxic lymphocytes sense and respond to high and low concentrations of drug-induced stress to the drug cisplatin, among the various types of drugs that contribute to their anticancer activity.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5243-5248
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• 2013

Background: Triptolide, extracted from the herb Tripteryglum wilfordii Hook.f that has long been used as a natural medicine in China, has attracted much interest for its anti-cancer effects against some kinds of tumours in recent years. Artesunate, extracted from the Chinese herb Artemisia annua, has proven to be effective and safe as an anti-malarial drug that possesses anticancer potential. The present study attempted to clarify if triptolide enhances artesunate-induced cytotoxicity in pancreatic cancer cell lines in vitro and in vivo. Methods: In vitro, to test synergic actions, cell viability and apoptosis were analyzed after treatment of pancreatic cancer cell lines with the two agents singly or in combination. The molecular mechanisms of apoptotic effects were also explored using qRT-PCR and Western blotting. In vivo, a tumor xenograft model was established in nude mice, for assessment of inhibitory effects of triptolide and artesunate. Results: We could show that the combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Conclusion: Our result indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications.

• BMB Reports
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• v.55 no.1
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• pp.48-56
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• 2022

Small extracellular vesicles (sEVs) secreted by most cells carry bioactive macromolecules including proteins, lipids, and nucleic acids for intercellular communication. Given that some immune cell-derived sEVs exhibit anti-cancer properties, these sEVs have received scientific attention for the development of novel anti-cancer immunotherapeutic agents. In this paper, we reviewed the latest advances concerning the biological roles of immune cell-derived sEVs for cancer therapy. sEVs derived from immune cells including dendritic cells (DCs), T cells, natural-killer (NK) cells, and macrophages are good candidates for sEV-based cancer therapy. Besides their role of cancer vaccines, DC-shed sEVs activated cytotoxic lymphocytes and killed tumor cells. sEVs isolated from NK cells and chimeric antigen receptor (CAR) T cells exhibited cytotoxicity against cancer cells. sEVs derived from CD8⁺ T and CD4⁺ T cells inhibited cancer-associated cells in tumor microenvironment (TME) and activated B cells, respectively. M1-macrophage-derived sEVs induced M2 to M1 repolarization and also created a pro-inflammatory environment. Hence, these sEVs, via mono or combination therapy, could be considered in the treatment of cancer patients in the future. In addition, sEVs derived from cytokine-stimulated immune cells or sEV engineering could improve their anti-tumor potency.

• Biomolecules & Therapeutics
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• v.3 no.2
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• pp.122-131
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• 1995

Five human cancer cell lines (HeLa S3, Hep 3B, KATO III, Hs 683, HeLa MR) and one human normal cell line (WI-38) were examined cell viability, northern blot analysis, western blot analysis, and in situ hybridization for the expression $O_{6}$ -methylguanine-DNAmethyltransferase (MGMT), which can repair $O_{6}$ -methylguanine produced in DNA by alkylating agents. In cell viability test, the lethal sensitivities of each strain against anti-tumor drug N,N-bis(2-chloroethyl)- N-nitrosourea (BCNU) were counted, and both BCNU treated and untreated cell extracts were examined for their MGMT inducibility by RNA dot blot analysis. Cell lines did not show MGMT induction by BCNU pretreatment. Tlle MGMT activity was assayed by measuring the $^3$H radioactivity transferred from the substrate DNA containing [methyl-$^3$H)-O$_{6}$ -methylguanine to acceptor molecules in the cell extracts. Extracts from the majority of tumor strains and normal cells contained substantial MGMT activity of varying degree, while the known Mer$^{[-10]}$ cell (lacked or severely depleted in MGMT activity) Hela MR, and Hs 683 (proved to be Mer$^{[-10]}$ ) were much more sensitive to BCNU than the rest of tumor strains, as measured by cell viability test. Overall results above, KATO III showed the highest expression level of MGMT among the strains examined. Furthermore, with all the tumor and normal strains tested, a good correlation was observed between MGMT expression and cellular resistance to BCNU. The varying levels of expression of MGMT in human cancer cells found in this study should provide a molecular basis for MGMT expression among tumor strains from different tissue origin, the information of antitumor agents selection for chemotherapy of cancers.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.23 no.2
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• pp.121-131
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• 2020

Purpose: To determine the long-term efficacy of the anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADA), in pediatric luminal Crohn's disease (CD) by performing a systematic literature review. Methods: An electronic search was performed in Medline, Embase, and the Cochrane Library from inception to September 26, 2019. Eligible studies were cohort studies with observation periods that exceeded 1 year. Studies that reported time-to-event analyses were included. Events were defined as discontinuation of anti-TNF therapy for secondary loss of response. We extracted the probabilities of continuing anti-TNF therapy 1, 2, and 3 years after initiation. Results: In total, 2,464 papers were screened, 94 were selected for full text review, and 13 studies (11 on IFX, 2 on ADA) met our eligibility criteria for inclusion. After 1 year, 83-97% of patients were still receiving IFX therapy. After 2 and 3 years the probability of continuing IFX therapy decreased to 67-91% and 61-85%, respectively. In total, 5 of the 11 studies subgrouped by concomitant medication consistently showed that the probabilities of continuing IFX therapy in patients with prolonged immunomodulator use were higher than those in patients on IFX monotherapy. Conclusion: This review of real-world evidence studies confirms the long-term therapeutic benefit of IFX therapy in diverse cohorts of children with luminal CD. Moreover, it supports the view that combination therapy with an immunomodulator prolongs the durability of IFX therapy in patients who previously failed to recover following first-line therapy. The limited number of time-to-event studies in patients on ADA prevented us from drawing definite conclusions about its long-term efficacy.

• Biomolecules & Therapeutics
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• v.20 no.1
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• pp.81-88
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• 2012

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents. In recent years, a number of structurally diverse HDAC inhibitors have been identifi ed and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. However, the underlying molecular mechanisms remain unclear. This study aimed at investigating the anti-tumor activity of various HDAC inhibitors, IN-2001, using T47D human breast cancer cells. Moreover, the possible mechanism by which HDAC inhibitors exhibit anti-tumor activity was also explored. In estrogen receptor positive T47D cells, IN-2001, HDAC inhibitor showed anti-proliferative effects in dose-and time-dependent manner. In T47D human breast cancer cells showed anti-tumor activity of IN-2001 and the growth inhibitory effects of IN-2001 were related to the cell cycle arrest and induction of apoptosis. Flow cytometry studies revealed that IN-2001 showed accumulation of cells at $G_2$/M phase. At the same time, IN-2001 treatment time-dependently increased sub-$G_1$ population, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with induction of cdk inhibitor expression. In T47D cells, IN-2001 as well as other HDAC inhibitors treatment significantly increased $p21^{WAF1}$ and $p27^{KIP1}$ expression. In addition, thymidylate synthase, an essential enzyme for DNA replication and repair, was down-regulated by IN-2001 and other HDAC inhibitors in the T47D human breast cancer cells. In summary, IN-2001 with a higher potency than other HDAC inhibitors induced growth inhibition, cell cycle arrest, and eventual apoptosis in human breast cancer possibly through modulation of cell cycle and apoptosis regulatory proteins, such as cdk inhibitors, cyclins, and thymidylate synthase.

• Journal of the Korean Chemical Society
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• v.34 no.4
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• pp.331-339
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• 1990

It has been studied that relations between electronic structure and anti-tumor activity by variation of amine group in cis-diamminedichloroplatinum (Ⅱ) complexes. We were also interested in these Pt (Ⅱ) complexes interaction with 1-methylcytosine of DNA base and the electronic structure of these complexes in order to understand the mechanism of the metal-nucleobases interaction. The results showed that net charge of center metal in Pt complexes effect anti-tumor activity. The mechanisgm of the bonding between metal and ligands largely based on charge transfer from ligand to metal atom. Furthermore, the established molecular orbitals showed that metal 6p-orbitals played an important role in the bonding scheme for the interactions between platinum (Ⅱ) complexes and 1-methylcytosine. We also found that the stronger Pt-N3 bonding strength became, the better anti-tumor agents were.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8177-8182
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• 2014

Background: Blocking angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling pathway to inhibit tumor growth has proven to be successful in treating a variety of different metastatic tumor types, including kidney, colon, ovarian, and lung cancers, but its role in castration-resistant prostate cancer (CRPC) is still unknown. We here aimed to determine the efficacy and toxicities of anti-VEGF agents in patients with CRPC. Materials and Methods: The databases of PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology up to March 31, 2014 were searched for relevant articles. Pooled estimates of the objective response rate (ORR) and prostate-specific antigen (PSA) response rate (decline ${\geq}50%$) were calculated using the Comprehensive Meta-Analysis (version 2.2.064) software. Median weighted progression-free survival (PFS) and overall survival (OS) time for anti-VEGF monotherapy and anti-VEGF-based doublets were compared by two-sided Student's t test. Results: A total of 3,841 patients from 19 prospective studies (4 randomized controlled trials and 15 prospective nonrandomized cohort studies) were included for analysis. The pooled ORR was 12.4% with a higher response rate of 26.4% (95%CI, 13.6-44.9%) for anti-VEGF-based combinations vs. 6.7% (95%CI, 3.5-12.7%) for anti-VEGF alone (p=0.004). Similarly, the pooled PSA response rate was 32.4% with a higher PSA response rate of 52.8% (95%CI: 40.2-65.1%) for anti-VEGF-based combinations vs. 7.3% (95%CI, 3.6-14.2%) for anti-VEGF alone (p<0.001). Median PFS and OS were 6.9 and 22.1 months with weighted median PFS of 5.6 vs. 6.9 months (p<0.001) and weighted median OS of 13.1 vs. 22.1 months (p<0.001) for anti-VEGF monotherapy vs. anti-VEGF-based doublets. Conclusions: With available evidence, this pooled analysis indicates that anti-VEGF monotherapy has a modest effect in patients with CRPC, and clinical benefits gained from anti-VEGF-based doublets appear greater than anti-VEGF monotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.5273-5279
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• 2012

The aim of the present study was to investigate the chemopreventive effect of coumarin against 7, 12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis by monitoring tumor incidence and histopathological changes as well as by analyzing the status of biochemical markers (lipid peroxidation, enzymatic and non-enzymatic antioxidants, phase I and phase II detoxification enzymes). Oral squamous cell carcinomas were induced in the buccal pouch of Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. We noted 100% tumor formation with marked abnormalities in the biomarkers status in hamsters treated with DMBA alone. Oral administration of coumarin at a dose of 100 mg/kg body weight (bw) to DMBA treated hamsters completely prevented the tumor formation as well as restored the staus of biochemical variables. The results of the present study thus suggest that the chemopreventive effect of coumarin is probably due to its anti-lipid peroxidative potential and modulating effect on carcinogen detoxification agents in favor of the excretion of ultimate carcinogenic metabolites of DMBA during DMBA-induced hamster buccal pouch carcinogenesis.

• Journal of Ginseng Research
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• v.48 no.3
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• pp.266-275
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• 2024

Cancer stem cells (CSCs) are a rare subpopulation of cancer cells that exhibit stem cell-like characteristics, including self-renewal and differentiation in a multi-stage lineage state via symmetric or asymmetric division, causing tumor initiation, heterogeneity, progression, and recurrence and posing a major challenge to current anticancer therapy. Despite the importance of CSCs in carcinogenesis and cancer progression, currently available anticancer therapeutics have limitations for eradicating CSCs. Moreover, the efficacy and therapeutic windows of currently available anti-CSC agents are limited, suggesting the necessity to optimize and develop a novel anticancer agent targeting CSCs. Ginseng has been traditionally used for enhancing immunity and relieving fatigue. As ginseng's long history of use has demonstrated its safety, it has gained attention for its potential pharmacological properties, including anticancer effects. Several studies have identified the bioactive principles of ginseng, such as ginseng saponin (ginsenosides) and non-saponin compounds (e.g., polysaccharides, polyacetylenes, and phenolic compounds), and their pharmacological activities, including antioxidant, anticancer, antidiabetic, antifatigue, and neuroprotective effects. Notably, recent reports have shown the potential of ginseng-derived compounds as anti-CSC agents. This review investigates the biology of CSCs and efforts to utilize ginseng-derived components for cancer treatment targeting CSCs, highlighting their role in overcoming current therapeutic limitations.