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1.
Mol Cancer ; 21(1): 52, 2022 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-35164788

RESUMEN

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.


Asunto(s)
Inteligencia Artificial , Neoplasias , Adenosina/química , Descubrimiento de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pronóstico
2.
Bioorg Med Chem Lett ; 65: 128717, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35390450

RESUMEN

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.


Asunto(s)
Productos Biológicos , Neoplasias , Inhibidores de la Angiogénesis/farmacología , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo
3.
Acta Pharm Sin B ; 14(2): 682-697, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38322324

RESUMEN

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

4.
Free Radic Biol Med ; 204: 301-312, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37217090

RESUMEN

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRASG13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRASG13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRASG13D with a Kd of 1.1163 µM, which also significantly improve the thermal stability of KRASG13D. The cell viability assay showed that KRASG13D cells were more sensitive to erianin than KRASWT or KRASG12V cells. In vitro, results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRASG13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe2+ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRASG13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRASG13D CRC.


Asunto(s)
Neoplasias Colorrectales , Ferroptosis , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Ferroptosis/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación , Autofagia
5.
Adv Sci (Weinh) ; 10(30): e2302717, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37635201

RESUMEN

Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium-based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel-associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease-free survival in CRC patients. Gain- and loss-of-function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial-mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte-conditional Tcaf2-knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro-metastatic effects of TPCs from the perspective of cold-sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Canales Catiónicos TRPM , Ratones , Animales , Humanos , Pericitos/metabolismo , Proteómica , Sensación Térmica , Neoplasias Colorrectales/genética , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Proteínas de la Membrana/metabolismo
6.
Life Sci ; 324: 121715, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37100377

RESUMEN

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Supresoras de Origen Mieloide , Humanos , Ratones , Animales , Carcinoma Hepatocelular/patología , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Hepáticas/patología , Células Supresoras de Origen Mieloide/metabolismo , Proliferación Celular , Apoptosis , Línea Celular Tumoral
7.
J Clin Invest ; 132(19)2022 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-35951441

RESUMEN

Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to antiangiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein α (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts. Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain- or loss-of-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2/FGFR1/ERK1/-2/EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in tumor tissues derived from patients with CRCLM. Targeting FAPα+ HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance. Our study highlights the role of FAPα+ HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Inhibidores de la Angiogénesis , Animales , Bevacizumab/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Endopeptidasas , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Células Estrelladas Hepáticas/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana , Ratones
8.
Curr Med Chem ; 26(18): 3341-3369, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-29446726

RESUMEN

BACKGROUND: Metal-organic frameworks (MOFs), as a new class of porous organic-inorganic crystalline hybrid materials that governed by the self-assembled of metal atoms and organic struts have attracted tremendous attention because of their special properties. Recently, some more documents have reported different types of nanoscale metal-organic frameworks (NMOFs) as biodegradable and physiological pH-responsive systems for photothermal therapy and radiation therapy in the body. DISCUSSION: In this review paper aims at describing the benefits of using MOF nanoparticles in the field of biomedicine, and putting into perspective their properties in the context of the ones of other NPs. The first section briefly reviews the biomaterial scaffolds of MOFs. The second section presents the main types of stimuli-responsive mechanisms and strategies from two categories: intrinsic (pH, redox state) and extrinsic (temperature, light irradiation and magnetic field) ones. The combinations of photothermal therapy and radiation therapy have been concluded in detail. Finally, clinical applications of MOFs, future challenges and perspectives are also mentioned. CONCLUSION: This review outlines the most recent advances MOFs design and biomedical applications, from different synthesis to their use as smart drug delivery systems, bioimaging technology or a combination of both.


Asunto(s)
Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Estructuras Metalorgánicas/química , Nanoestructuras/química , Animales , Terapia Combinada/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Estructuras Metalorgánicas/farmacología , Nanoestructuras/toxicidad , Imagen Óptica/métodos , Fototerapia/métodos , Radioterapia/métodos
9.
RSC Adv ; 8(42): 23529-23538, 2018 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-35540252

RESUMEN

A new Pb(ii)-based 2D MOF comprising π-conjugated ligand 4'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3,5-dicarboxylic acid (TZBPDC) and having the formula {[PbNa(TZBPDC)](H2O)(DMF)2} n (1) has been synthesized. Structural characterization of 1 indicates that the MOF has a 4-connected (4,4) motif. The photoluminescent investigation indicates that 1 can behave as potential luminescent sensor for the detection of nitroaromatic compounds (NACs), especially 2,4-dinitrophenol (2,4-DNP) and ferric ions, through the decrease in its luminescence intensity. Additionally, 1 also displays excellent capacity for the photodegradation of methylene orange (MO), which is a constituent of wastewater discharge. The most plausible mechanisms for the decrease in the luminescent intensity of 1 in the presence of different NACs have been explored though theoretical calculations, and the photocatalysis of 1 for organic dyes has been addressed using density of states (DOS) and partial DOS calculations.

10.
Polymers (Basel) ; 10(2)2018 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-30966245

RESUMEN

We herein selected a 3D metal⁻organic framework decorated with carboxylate groups as an adsorbent to remove the pharmaceutical molecules of diclofenac sodium and chlorpromazine hydrochloride from water. The experiment aimed at exploring the effect factors of initial concentration, equilibrium time, temperature, pH and adsorbent dosage on the adsorption process. The adsorption uptake rate of the diclofenac sodium is much higher than that of the chlorpromazine hydrochloride. This paper presents the high adsorption capacity of diclofenac sodium, in which porous MOFs are used for the removal of drug contaminants from water. According to linear fitting with adsorption isotherm equation and kinetic equations, diclofenac sodium conforms to the Langmuir model and pseudo-first-order kinetic equation, while chlorpromazine hydrochloride accords with the Temkin model and pseudo-second-order kinetic equation. The results of the study indicate that the title compound could be a promising hybrid material for removing diclofenac sodium and chlorpromazine hydrochloride from wastewater.

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