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1.
Cancer Chemother Pharmacol ; 93(5): 411-425, 2024 May.
Article in English | MEDLINE | ID: mdl-38191768

ABSTRACT

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.


Subject(s)
Apoptosis , Artemisinins , Colonic Neoplasms , G1 Phase Cell Cycle Checkpoints , Humans , Artemisinins/pharmacology , Artemisinins/chemistry , Apoptosis/drug effects , Colonic Neoplasms/pathology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/immunology , G1 Phase Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Adaptive Immunity/drug effects , Ruthenium/chemistry , Ruthenium/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , HCT116 Cells , HT29 Cells , Animals , Cytokines/metabolism , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Mice
2.
Cell Rep Med ; 4(11): 101289, 2023 11 21.
Article in English | MEDLINE | ID: mdl-37992685

ABSTRACT

The clinical utility of human interleukin-2 (hIL-2) is limited by its short serum half-life, preferential activation of regulatory T (TReg) over immune effector cells, and dose-limiting toxicities. We previously engineered F10 immunocytokine (IC), an intramolecularly assembled cytokine/antibody fusion protein that linked hIL-2 to an anti-IL-2 antibody (denoted F10) that extended IL-2 half-life and augmented the immune effector to TReg ratio. Here, we leveraged molecular engineering to improve the anti-tumor therapeutic efficacy and tolerability of F10 IC by developing an iteration, denoted F10 IC-CBD (collagen binding domain), designed for intratumoral administration and in situ retention based on collagen affinity. F10 IC-CBD retained IL-2 bioactivity exclusively in the tumor and eliminated IL-2-associated toxicities. Furthermore, F10 IC exhibited potent single-agent therapeutic efficacy and synergy with systemic immune checkpoint blockade and elicited an abscopal response in mouse tumors models. This engineered fusion protein presents a prototype for the design of intratumoral therapies.


Subject(s)
Interleukin-2 , Neoplasms , Humans , Mice , Animals , Interleukin-2/genetics , Interleukin-2/pharmacology , Interleukin-2/therapeutic use , Biological Availability , Collagen
3.
Mol Biol Rep ; 49(4): 2695-2709, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35040004

ABSTRACT

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.


Subject(s)
Artemisinins , Colonic Neoplasms , Apoptosis , Artemisinins/pharmacology , Chemoprevention , Colonic Neoplasms/drug therapy , Colonic Neoplasms/prevention & control , Humans
4.
J Appl Biomed ; 19(2): 113-124, 2021.
Article in English | MEDLINE | ID: mdl-34754259

ABSTRACT

Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 µM and 15.5 µM, respectively. In the mechanistic study, after treatment with 5 µg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.


Subject(s)
Colonic Neoplasms , Oplopanax , Apoptosis , Cell Cycle Checkpoints , Chemoprevention , Cyclin A/pharmacology , Cyclins/pharmacology , Diynes , Fatty Alcohols , Humans , Methylene Chloride/pharmacology , Oplopanax/chemistry , Up-Regulation
5.
Data Brief ; 21: 1403-1408, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30456264

ABSTRACT

Although anti-inflammatory effects of American ginseng metabolites have been investigated at systemic and cellular levels, the biological signatures of ginseng microbial metabolite-induced bioactivities are still unknown. To fill this knowledge gap and to support the findings published in the companion research article entitled "American ginseng microbial metabolites attenuated DSS-induced colitis and abdominal pain" (Wang et al., 2018), we are here to provide datasets of enteric microbiome biotransformation and fecal metabolomics. For the microbiome biotransformation study, data were obtained from C57BL6 mice treated with a broad-spectrum antibiotic metronidazole. After oral administration of ginseng extract, we observed that compound K (CK) was undetectable in metronidazole-treated mouse stools but was detected in stools from vehicle-treated mice, suggesting biotransformation of CK is gut microbial dependent. In the fecal metabolomic study, three small molecules which were associated with gut inflammation were identified. In the DSS mice, the levels of lactate, linoleic acid, and malic acid increased significantly in the model group. After ginseng treatment, the expressions of these metabolites reduced significantly. Thus, the selective fecal endogenous metabolites could be used as biological signatures reflecting severity of enteric inflammation and ginseng treatment outcomes. Our results showed the enteric microbiome plays a key role for CK conversion, and the effects of CK on enteric inflammation can be demonstrated by the metabolomics data.

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