• Journal of the Korean Applied Science and Technology
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• v.35 no.4
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• pp.1386-1392
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• 2018

Cispatin has become one of the most widely used anticancer drugs for decades. One of the drawback of cisplatin (II) complex is that it not only targets cancerous cells but also normal cells causing several serious side effects in patients. We have synthesized Pt(IV) complex that are needed to have the ability to kill target cells selectively in a short time before drug resistance develops. By introducing PDK inhibitor, butyric acid and valproic acid, on Pt complex, two fusion anti-cancer agents 3 and 4 have been synthesized and characterized their structures by nmr and mass spectrometer. MTT assay was performed with $Pt(IV)-Bu_2$ 3 and $Pt(IV)-Val_2$ 4 against MCF-7 cell line. As a result, cisplatin, Pt(IV) complexes 3 and 4 were treated, cell viabilities at $50{\mu}M$ cencentration were decreased to 39%, 54% and 84% respectively.

• Molecules and Cells
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• v.42 no.4
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• pp.292-300
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• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

• Journal of Pharmacopuncture
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• v.22 no.2
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• pp.90-94
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• 2019

Objectives: Paclitaxel (PTX) as an anticancer drug used against solid cancers, possesses adverse reactions such as neuropathic pain which has confined its use. PTX-induced neuropathic pain is mediated via activation of oxidative stress. Berberine (BER), an isoquinoline phytochemical found in several plants, exerts strong antioxidant and painkilling properties. In the current study, we aimed to evaluate pain-relieving effect of BER in a mouse model of PTX-induced neuropathic pain. Methods: This study was done using 42 male albino mice that were randomly divided into 6 groups (n = 7) as follow: Sham-operated (not treated with PTX), negative control group (PTX-treated mice receiving normal saline), BER 5, 10, and 20 mg/kg (PTX-treated mice receiving BER) and positive control group (PTX-treated mice receiving imipramine 10 mg/kg). Neuropathic pain was induced by intraperitoneal administration of four doses of PTX (2 mg/kg/day) on days 1, 3, 5 and 7. Then, on day 7, hot plate test was done to assess latency to heat to measure possible anti-neuropathic pain effect of BER. Results: Four doses of PTX 2 mg/kg/day induced neuropathy that was reduced by BER at all time-points (i.e. 0, 30, 60, 90 and 120 min) after injection (P < 0.001 in comparison to control). The statistical analysis of data showed significant differences between groups (P < 0.001 in comparison to negative control), at 30, 60, 90 and 120 min after injection of BER 5, 10 and 20 mg/kg; in other words, 30, 60, 90 and 120 min after BER administration, neuropathic pain was significantly reduced as compared to normal saline-treated mice. Conclusion: Altogether, our results showed that PTX could induce neuropathic pain as reflected by hyperalgesia and BER could alleviate PTX-induced thermal hyperalgesia.

• Journal of Pharmacopuncture
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• v.22 no.2
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• pp.102-108
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• 2019

Objectives: Esophageal squamous cell carcinoma (ESCC) is considered as a deadly medical condition that affects a growing number of people worldwide. Targeted therapy of ESCC has been suggested recently and required extensive research. With cyclin D1 as a therapeutic target, the present study aimed at evaluating the anticancer effects of doxorubicin (Dox) or Hypericum perforatum L. (HP) extract encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles on the ESCC cell line KYSE30. Methods: Nanoparticles were prepared using double emulsion method. Cytotoxicity assay was carried out to measure the anti-proliferation activity of Dox-loaded (Dox NPs) and HP-loaded nanoparticles (HP NPs) against both cancer and normal cell lines. The mRNA gene expression of cyclin D1 was evaluated to validate the cytotoxicity studies at molecular level. Results: Free drugs and nanoparticles significantly inhibited KYSE30 cells by 55-73% and slightly affected normal cells up to 29%. The IC50 of Dox NPs and HP NPs was ~ 0.04-0.06 mg/mL and ~ 0.6-0.7 mg/mL, respectively. Significant decrease occurred in cyclin D1 expression by Dox NPs and HP NPs (P < 0.05). Exposure of KYSE-30 cells to combined treatments including both Dox and HP extract significantly increased the level of cyclin D1 expression as compared to those with individual treatments (P < 0.05). Conclusion: Dox NPs and HP NPs can successfully and specifically target ESCC cells through downregulation of cyclin D1. The simultaneous use of Dox and HP extract should be avoided for the treatment of ESCC.

• Journal of Food Hygiene and Safety
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• v.36 no.1
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• pp.100-104
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• 2021

trans-Cinnamaldehyde (TCA), as one of the active ingredients in cinnamon, has been reported to have antiviral, antibacterial and antifungal effects as well as anti-cancer effects in several cancer cell lines. However, reports of TCA in gastric cancer are rare, and its mechanism is unclear. In this study, we investigated the anti-proliferative effect of TCA and its mechanism in gastric cancer AGS cells. TCA dose-dependently inhibited the cell viability of AGS cells. Our results suggested that TCA induces apoptosis through changes in cell morphology. To elucidate its mechanism, we investigated the expression level of apoptosis-related proteins. TCA induced the expression of p53 and Bax proteins, and then increased the cleaved caspase 9 and cleaved PARP. These results indicated that TCA triggers apoptosis via p53 pathway in AGS cells. Our results suggested that TCA might be a new anticancer drug candidate for gastric cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.1
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• pp.15-24
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• 2022

The development of selective targeting of drug molecules towards the mitochondria is an important issue related to therapy efficacy. In this study, we report that gallic acid (GA)-mitochondria targeting sequence (MTS)-H₃R₉ exhibits a dual role as a mitochondria-targeting vehicle with antioxidant activity for disease therapy. In viability assays, GA-MTS-H₃R₉ showed a better rescue action compared to that of MTS-H₃R₉. GA-MTS-H₃R₉ dramatically exhibited cell penetration and intercellular uptake compared to MTS and fit escape from lysosome release to the cytosol. We demonstrated the useful targeting of GA-MTS-H₃R₉ towards mitochondria in AC16 cells. Also, we observed that the antioxidant properties of mitochondrial-accrued GA-MTS-H₃R₉ alleviated cell damage by reactive oxygen species production and disrupted mitochondrial membrane potential. GA-MTS-H₃R₉ showed a very increased cytoprotective effect against anticancer activity compared to that of MTS-H₃R₉. We showed that GA-MTS-H₃R₉ can act as a vehicle for mitochondria-targeting and as a reagent for therapeutic applications intended for cardiovascular disease treatment.

• International Journal of Oral Biology
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• v.47 no.1
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• pp.9-15
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• 2022

Humulus japonicus (HJ) is a widely used herbal medicine for pulmonary tuberculosis, hypertension, leprosy, and venomous wounds in Asia, particularly in China. Although HJ has certain physiological activities, such as longitudinal bone growth, antioxidation and alleviation of rheumatism, its anticancer activities, other than in colorectal and ovarian cancer, are yet to be studied. In this study, we investigated the anti-cancer activity and mechanism of methanol extracts of HJ (MeHJ) against human FaDu hypopharyngeal squamous carcinoma cells. MeHJ suppressed FaDu cell viability without affecting normal cells (L929), which was demonstrated using the MTT and Live & Dead assays. Furthermore, MeHJ effectively inhibited colony formation of FaDu cells, even at non-cytotoxic concentrations, and significantly induced apoptosis through the proteolytic cleavage of caspase-9, -3, -7, poly (ADP-ribose) polymerase and through the downregulation of BCL-2 and upregulation of BAX in FaDu cells, as determined by DAPI staining, flow cytometry, and western blot analyses. Collectively, these findings suggest that the inhibitory effects of MeHJ on the growth and colony formation of oral cancer cells may be mediated by caspase- and mitochondrial-dependent apoptotic pathways in human FaDu hypopharyngeal squamous carcinoma cells. Therefore, MeHJ has the potential to be used as a natural chemotherapeutic drug against human oral cancer.

• International Journal of Oral Biology
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• v.46 no.4
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• pp.160-167
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• 2021

Nypa fruticans Wurmb (NFW) contains a large amount of phenolic acid and flavonoids, and is popular as a superfood in Myanmar. NFW has various biological activities, such as anti-inflammatory, anti-oxidant, and neuroprotective properties; however, the anti-cancer effect of NFW have not been reported. In this study, we investigated the anticancer activity of water extracts of NFW (WeNFW) and the underlying mechanism in human FaDu hypopharyngeal squamous carcinoma cells. The WeNFW inhibited FaDu cell growth in a dose-dependent manner without affecting normal cells (L929), as determined by an MTT assay and Live and Dead assay. In addition, the concentrations of WeNFW without cytotoxicity (0.025, 0.05, and 0.1 mg/mL) inhibited wound healing and colony formation. Furthermore, WeNFW significantly induced apoptosis through the proteolytic cleavage of caspase-3 and -9, poly (ADP-ribose) polymerase, and downregulation of Bcl-2 and upregulation of Bax in FaDu cells, as determined by DAPI staining, FACS analysis, and western blot analysis. Taken together, these results suggest that WeNFW exhibits potent anti-cancer effects by suppressing the growth of oral cancer cells, wound healing and colony formation activity. Via mitrochondrial-dependent apoptotic pathways in human FaDu hypopharyngeal squamous carcinoma cells. Therefore, WeNFW can provide a natural chemotherapeutic drug for oral cancer in humans.

• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.520-528
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• 2022

Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC₅₀, approx. 0.58 μM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC₅₀, approx. 0.09 μM) and TNF-α (IC₅₀, approx. 0.19 μM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

• BMB Reports
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• v.55 no.10
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• pp.506-511
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• 2022

Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.