Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 36
Filter
Add more filters










Publication year range
1.
BMC Microbiol ; 24(1): 8, 2024 Jan 03.
Article in English | MEDLINE | ID: mdl-38172689

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial. METHODS: In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria. RESULTS: Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS: In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.


Subject(s)
Bifidobacterium longum , Gastrointestinal Microbiome , Animals , Humans , Mice , Brain-Gut Axis , Irinotecan/metabolism , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/pharmacology
2.
Molecules ; 28(7)2023 Apr 04.
Article in English | MEDLINE | ID: mdl-37049985

ABSTRACT

There have been many attempts in pharmaceutical industries and academia to improve the pharmacokinetic characteristics of anti-tumor small-molecule drugs by conjugating them with large molecules, such as monoclonal antibodies, called ADCs. In this context, albumin, one of the most abundant proteins in the blood, has also been proposed as a large molecule to be conjugated with anti-cancer small-molecule drugs. The half-life of albumin is 3 weeks in humans, and its distribution to tumors is higher than in normal tissues. However, few studies have been conducted for the in vivo prepared albumin-drug conjugates, possibly due to the lack of robust bioanalytical methods, which are critical for evaluating the ADME/PK properties of in vivo prepared albumin-drug conjugates. In this study, we developed a bioanalytical method of the albumin-conjugated MAC glucuronide phenol linked SN-38 ((2S,3S,4S,5R,6S)-6-(4-(((((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3',4':6,7] indolizino [1,2-b] quinolin-9-yl)oxy)methyl)(2 (methylsulfonyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylpropanamido)acetamido)phenoxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid) as a proof-of-concept. This method is based on immunoprecipitation using magnetic beads and the quantification of albumin-conjugated drug concentration using LC-qTOF/MS in mouse plasma. Finally, the developed method was applied to the in vivo intravenous (IV) mouse pharmacokinetic study of MAC glucuronide phenol-linked SN-38.


Subject(s)
Albumins , Immunoprecipitation , Irinotecan , Liquid Chromatography-Mass Spectrometry , Animals , Humans , Mice , Albumins/chemistry , Albumins/pharmacokinetics , Glucuronidase/metabolism , Glucuronides/chemistry , Glucuronides/metabolism , Immunoprecipitation/methods , Irinotecan/blood , Irinotecan/chemistry , Irinotecan/metabolism , Irinotecan/pharmacokinetics , Liquid Chromatography-Mass Spectrometry/methods , Magnetics , Phenol/chemistry
3.
Arch Microbiol ; 205(5): 179, 2023 Apr 08.
Article in English | MEDLINE | ID: mdl-37029820

ABSTRACT

Pogostemon cablin (Blanco) Benth (PCB), a medicinal and edible homologous Chinese herb, has a protective effect on the structure and function of intestine. In this study, we aimed to investigate the effect of PCB granule (PCBG) on the improvement of irinotecan-induced intestinal mucositis and the regulation of intestinal microorganisms in mice. Our results demonstrated that PCBG supplementation significantly improved diarrhea symptoms caused by irinotecan, as evidenced by inhibiting weight loss, reversing intestinal atrophy, protecting against splenomegaly and balancing oxidative stress. Furthermore, compared with the model group, PCBG restored the intestinal morphology and improved intestinal barrier dysfunction by promoting the expression of tight junction proteins and mucin. Moreover, high-throughput sequencing analysis revealed that PCBG improved the flora disorder caused by irinotecan and regulated microbial community structure, such as decreasing the relative abundance of Bacteroides as well as increasing the relative abundance of Lactobacillus. Meanwhile, the disordered microbial functions in intestinal mucositis mice were recovered more closely to the controls by PCBG. Finally, we found that a robust correlation between the specific microbiota and intestinal mucositis-related index. In summary, these findings revealed the beneficial effects of PCBG on the intestinal barrier and gut microbiota of irinotecan-induced intestinal mucositis, which may be one of the potential strategies to reduce the clinical side effects of irinotecan.


Subject(s)
Gastrointestinal Microbiome , Mucositis , Pogostemon , Mice , Animals , Mucositis/chemically induced , Mucositis/drug therapy , Mucositis/metabolism , Irinotecan/adverse effects , Irinotecan/metabolism , Intestinal Mucosa , Intestines
4.
Eur J Oral Sci ; 131(2): e12922, 2023 04.
Article in English | MEDLINE | ID: mdl-36852977

ABSTRACT

Taste alteration is a frequently reported side effect in patients receiving the chemotherapeutic agent, irinotecan. However, the way in which irinotecan causes taste disturbance and the type of taste impairment that is affected remain elusive. Here, we used the two-bottle preference test to characterize behavioral taste responses and employed immunohistochemical analyses to clarify the types and mechanisms of taste alteration induced, in mice, by irinotecan administration. Irinotecan administration resulted in a reduced intake of sodium taste solution but had no effect on sweet taste responses, as determined in the two-bottle preference test. In the presence of amiloride, which inhibits the function of the epithelial sodium channel (ENaC) in the periphery, the intake of sodium taste solution was comparable between the irinotecan-treated and control groups. Immunohistochemical analyses revealed that α-ENaC immunoreactivity detected in taste bud cells decreased slowly after irinotecan administration, and that administration of irinotecan had little effect on the number of cells expressing the cellular proliferation marker, Ki67, within or around taste buds. Our results imply that irinotecan administration may be responsible for altered behavioral sodium taste responses originating from ENaC function in the periphery, while being accompanied by the reduction of α-ENaC expression at the apical membrane of taste receptor cells without disturbing taste cell renewal.


Subject(s)
Amiloride , Taste Buds , Mice , Animals , Amiloride/pharmacology , Amiloride/metabolism , Sodium/metabolism , Sodium/pharmacology , Taste , Irinotecan/metabolism , Irinotecan/pharmacology , Dysgeusia
5.
Chem Biol Interact ; 368: 110248, 2022 Dec 01.
Article in English | MEDLINE | ID: mdl-36343684

ABSTRACT

UGT1A1 is the main enzyme that catalyzes the metabolic elimination and detoxification of SN-38, the active form of the drug irinotecan. Milk thistle products have been used widely to protect the liver from injury associated with the use of chemotherapeutic agents. To evaluate whether SN-38 metabolism can be affected by milk thistle products, the inhibitory effects of silybins on UGT1A1*1 and UGT1A1*6 were evaluated in the present investigation. Both silybin A and silybin B potently inhibited SN-38 glucuronidation catalyzed by UGT1A1*1 or UGT1A1*6. It was noteworthy that silybin A and silybin B showed synergistic effect in UGT1A1*1 microsomes at concentration around IC50, while additive effect in UGT1A1*6. According to the predicted AUCi/AUC ratios (the ratio of the area under the plasma concentration-time curve of SN-38 in the presence and absence of silybins), the coadministration of irinotecan and several milk thistle products, including silybin-phosphatidylcholine complex, two Legalon capsules, four Silymarin tablets or four Liverman capsules, may lead to clinically significant herb-drug interactions (HDI) via UGT1A1 inhibition. Meanwhile, Rgut values were much higher than 11 in all the groups, indicating potential HDI due to intestinal UGT1A1 inhibition.


Subject(s)
Glucuronosyltransferase , Silybum marianum , Irinotecan/metabolism , Silybin/metabolism , Silybin/pharmacology , Glucuronosyltransferase/metabolism , Microsomes, Liver/metabolism , Catalysis , Camptothecin
6.
Int J Oncol ; 60(3)2022 03.
Article in English | MEDLINE | ID: mdl-35059735

ABSTRACT

With >1.85 million cases and 850,000 deaths annually, colorectal cancer (CRC) is the third most common cancer detected globally. CRC is an aggressive malignancy with metastasis and, in spite of advances in improved treatment regimen, distant disease failure rates remain disappointingly high. Mucin­like 1 (MUCL1) is a small glycoprotein highly expressed mainly in breast cancer. The involvement of the MUCL1 protein in CRC progression and the underlying mechanism have been largely unknown. The aim of the present study was to investigate the MUCL1 expression profile and its functional significance in CRC. The Cancer Genome Atlas dataset revealed that MUCL1 expression was higher in colorectal tumor compared with normal tissues. MUCL1 was also revealed to be expressed in human CRC cell lines. The results demonstrated that MUCL1 promoted cell proliferation and colony formation, confirming its oncogenic potential. Silencing MUCL1 with short interfering RNA inhibited the protein expression of Bcl2 family proteins, such as Bcl2 and BclxL. Targeting MUCL1 resulted in significant inhibition in cell invasive and migratory behavior of HT­29 and SW620 cells. In addition, the expression of E­cadherin increased whereas the expression of vimentin decreased in MUCL1­silenced cells, confirming inhibition of epithelial­mesenchymal transition (EMT) process. Thus, it was revealed that MUCL1 plays a notable role in cell invasion and migration by inhibiting EMT in CRC. Mechanistically, MUCL1 drives ß­catenin activation by Ser­552 phosphorylation, nuclear accumulation and transcriptional activation. Targeting MUCL1 increases the drug sensitivity of CRC cells towards irinotecan. These findings thus demonstrated that MUCL1 acts as a modifier of other pathways that play an important role in CRC progression and MUCL1 was identified as a potential target for CRC therapeutics.


Subject(s)
Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Irinotecan/metabolism , Mucins/pharmacology , beta Catenin/drug effects , Cell Line/drug effects , Cell Line/physiology , Cell Movement/genetics , Colorectal Neoplasms/physiopathology , Humans , Irinotecan/pharmacology , Mucins/metabolism
7.
Biomed Pharmacother ; 144: 112317, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34634556

ABSTRACT

Irinotecan (IRN) is a semisynthetic derivative of camptothecin that acts as a topoisomerase I inhibitor. IRN is used worldwide for the treatment of several types of cancer, including colorectal cancer, however its use can lead to serious adverse effects, as diarrhea and myelosuppression. Liposomes are widely used as drug delivery systems that can improve chemotherapeutic activity and decrease side effects. Liposomes can also be pH-sensitive to release its content preferentially in acidic environments, like tumors, and be surface-functionalized for targeting purposes. Herein, we developed a folate-coated pH-sensitive liposome as a drug delivery system for IRN to reach improved tumor therapy without potential adverse events. Liposomes were prepared containing IRN and characterized for particle size, polydispersity index, zeta potential, concentration, encapsulation, cellular uptake, and release profile. Antitumor activity was investigated in a murine model of colorectal cancer, and its toxicity was evaluated by hematological/biochemical tests and histological analysis of main organs. The results showed vesicles smaller than 200 nm with little dispersion, a surface charge close to neutral, and high encapsulation rate of over 90%. The system demonstrated prolonged and sustained release in pH-dependent manner with high intracellular drug delivery capacity. Importantly, the folate-coated pH-sensitive formulation had significantly better antitumor activity than the pH-dependent system only or the free drug. Tumor tissue of IRN-containing groups presented large areas of necrosis. Furthermore, no evidence of systemic toxicity was found for the groups investigated. Thus, our developed nanodrug IRN delivery system can potentially be an alternative to conventional colorectal cancer treatment.


Subject(s)
Colorectal Neoplasms/drug therapy , Folic Acid/metabolism , Irinotecan/administration & dosage , Lipids/chemistry , Topoisomerase I Inhibitors/administration & dosage , Animals , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Delayed-Action Preparations , Drug Compounding , Drug Liberation , Folic Acid/chemistry , Hydrogen-Ion Concentration , Irinotecan/chemistry , Irinotecan/metabolism , Liposomes , Mice, Inbred BALB C , Necrosis , Time Factors , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/metabolism , Tumor Burden/drug effects
8.
Int J Mol Sci ; 22(18)2021 Sep 18.
Article in English | MEDLINE | ID: mdl-34576262

ABSTRACT

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN-38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN-38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II ß and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN-38 (CSN-38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN-38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN-38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.


Subject(s)
Antineoplastic Agents/chemistry , Breast Neoplasms/drug therapy , Cannabidiol/chemistry , Proteomics/methods , Adenocarcinoma/metabolism , Antineoplastic Agents/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis , Breast Neoplasms/metabolism , Cannabidiol/metabolism , Cell Line, Tumor , Cell Survival , Dactinomycin/analogs & derivatives , Dactinomycin/pharmacology , Docetaxel/chemistry , Docetaxel/metabolism , Doxorubicin/chemistry , Doxorubicin/metabolism , Drug Screening Assays, Antitumor , Drug Synergism , Female , Humans , Irinotecan/chemistry , Irinotecan/metabolism , MCF-7 Cells , Paclitaxel/chemistry , Paclitaxel/metabolism , Proteome , Vinorelbine/chemistry , Vinorelbine/metabolism
9.
Hum Cell ; 34(3): 889-900, 2021 May.
Article in English | MEDLINE | ID: mdl-33677798

ABSTRACT

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare disease with a poor prognosis. The lack of established disease models has hampered therapy development. We generated a panel of cancer tissue-originated spheroid (CTOS) lines derived from SCNEC of the uterine cervix using a method based upon cell-cell contact throughout the preparation and culturing processes. Using 11 CTOS lines, we assessed the sensitivity of various drugs used in clinical practice. Drug sensitivity assays revealed significant heterogeneous inter-CTOS chemosensitivity. Microarray analyses were then performed to identify sensitivity-related gene signatures. Specific gene sets were identified which likely contribute to the sensitivity to the tested drugs. We identified a line (Cerv54) that was exceptionally sensitive to irinotecan. Cerv54 had increased levels of CES1, which catalyzes the conversion of irinotecan to the active form, SN38, although in Cerv54 cells, SN38 was undetectable, CES1 expression and activity were markedly low compared to the liver, and a CES1 inhibitor had no effect on irinotecan sensitivity. These results suggested a novel irinotecan mode of action in Cerv54. Our CTOS lines may be useful for understanding the variation and mechanism of drug sensitivity, contributing to the understanding and development of chemotherapeutic drugs.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Neuroendocrine/pathology , Carcinoma, Small Cell/pathology , Drug Resistance, Neoplasm/genetics , Organoids/pathology , Uterine Cervical Neoplasms/pathology , Carboxylic Ester Hydrolases/genetics , Carboxylic Ester Hydrolases/metabolism , Carboxylic Ester Hydrolases/physiology , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/metabolism , Carcinoma, Small Cell/genetics , Carcinoma, Small Cell/metabolism , Catalysis , Cell Culture Techniques , Cell Line, Tumor , Female , Gene Expression , Humans , Irinotecan/metabolism , Irinotecan/pharmacology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/metabolism
10.
Cell Mol Life Sci ; 78(5): 2329-2339, 2021 Mar.
Article in English | MEDLINE | ID: mdl-32979053

ABSTRACT

Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/chemistry , Cholesterol/chemistry , Membrane Lipids/chemistry , Molecular Dynamics Simulation , Neoplasm Proteins/chemistry , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Binding Sites/genetics , Biological Transport , Cholesterol/metabolism , Humans , Irinotecan/chemistry , Irinotecan/metabolism , Membrane Lipids/metabolism , Mutation , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Protein Binding , Protein Domains
11.
J Mater Chem B ; 9(1): 187-194, 2021 01 07.
Article in English | MEDLINE | ID: mdl-33237120

ABSTRACT

In this study, an enhanced anticancer strategy combining the chemotherapy from antineoplastics with the oxidative damage from a sulfur dioxide (SO2) prodrug is presented. Based on the characteristics of a high glutathione (GSH) level in the tumor microenvironment, a novel GSH-responsive SO2 polymeric prodrug mPEG-b-P(PA-alt-GDNs) was designed and synthesized via a ring-opening alternating copolymerization and "click" reaction. The GSH-sensitive mechanism of the polymer was investigated in detail. Furthermore, Irinotecan was loaded into the polymeric prodrug nanoparticles by a self-assembly method with a drug loading content of 12.3 wt% and a loading efficiency of 42.2%. The drug-loaded nanoparticles showed a sensitive response to high concentrations of GSH in the tumor cells and rapidly released both Irinotecan and SO2. The depletion of GSH and the release of SO2 were supposed to increase the level of reactive oxygen species in the tumor cell, which, in combination with the released Irinotecan, exerted an enhanced anti-proliferative effect against HepG2 cells. Finally, Irinotecan-loaded nanoparticles exhibited a stronger antitumor effect than free antineoplastics in HepG2 cells. Thus, these results indicated that our polymeric prodrug SO2 is a promising candidate for chemotherapeutic drug delivery and would be a new weapon in anticancer treatment.


Subject(s)
Drug Delivery Systems/methods , Glutathione/chemical synthesis , Irinotecan/chemical synthesis , Polyethylene Glycols/chemical synthesis , Prodrugs/chemical synthesis , Sulfur Dioxide/chemical synthesis , Dose-Response Relationship, Drug , Glutathione/administration & dosage , Glutathione/metabolism , Hep G2 Cells , Humans , Irinotecan/administration & dosage , Irinotecan/metabolism , Nuclear Magnetic Resonance, Biomolecular/methods , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/metabolism , Polymers/administration & dosage , Polymers/chemical synthesis , Polymers/metabolism , Prodrugs/administration & dosage , Prodrugs/metabolism , Sulfur Dioxide/administration & dosage , Sulfur Dioxide/metabolism
12.
Drug Deliv ; 27(1): 1491-1500, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33100060

ABSTRACT

Gastric cancer is a frequently occurring cancer with high mortality each year worldwide. Finding new and effective therapeutic strategy against human gastric cancer is still urgently required. Hence, we have established a new method to achieve treatment-actuated modifications in a tumor microenvironment by utilizing synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and Camptothecin-11 (CPT-11) exhibits a great anti-cancer potential, as GEM enhances the effect of CPT-11 treatment of human gastric cells by providing microenvironment stability. However, encapsulation of GEM and CPT-11 obsessed by poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) is incompetent owing to unsuitability between the binary free GEM and CPT-11 moieties and the polymeric system. Now, we display that CPT-11 can be prepared by hydrophobic covering of the drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered CPT-11 can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the CPT-11 suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-CPT-11 NPs). Formation of the nanocomposite (GEM-CPT-11 NPs) was confirmed by FTIR and X-ray spectroscopic techniques. Further, the morphology of GEM NPs, CPT-11 NPs, and GEM-CPT-11 NPs and NP size was examined by transmission electron microscopy (TEM), respectively. Furthermore, GEM-CPT-11 NPs induced significant apoptosis in human gastric NCI-N87 and SGC-791 cancer cells in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In addition, evaluation of the hemolysis assay with erythrocytes of human shows excellent biocompatibility of free GEM, free CPT-11, GEM NPs, CPT-11 NPs, and GEM-CPT-11 NPs. The results suggest that GEM-CPT-11 NPs are one of the promising nursing cares for human gastric cancer therapeutic candidates worthy of further investigations.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Deoxycytidine/analogs & derivatives , Drug Delivery Systems/methods , Irinotecan/administration & dosage , Stomach Neoplasms/drug therapy , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/metabolism , Antineoplastic Combined Chemotherapy Protocols/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Deoxycytidine/administration & dosage , Deoxycytidine/metabolism , Dose-Response Relationship, Drug , Humans , Irinotecan/metabolism , Stomach Neoplasms/metabolism , Treatment Outcome , Gemcitabine
13.
Chem Biol Interact ; 332: 109295, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-33096057

ABSTRACT

Irinotecan (CPT11) is widely prescribed for treatment of various intractable cancers such as advanced and metastatic colon cancer cells, but its continuous treatment promotes the resistance development. In this study, we established CPT11-resistant variants of three human colon cancer (DLD1, RKO and LoVo) cell lines, and found that gain of the resistance elicited an up-regulation of aldo-keto reductase (AKR) 1C3 in the cells. Additionally, the sensitivity to CPT11 toxicity was decreased and increased by overexpression and knockdown, respectively, of the enzyme. Moreover, the resistant cells suppressed formation of reactive 4-hydroxy-2-nonenal by CPT11 treatment, and the suppressive effect was almost completely abolished by addition of an AKR1C3 inhibitor. These results suggest that up-regulated AKR1C3 contributes to promotion of the chemoresistance by detoxifying the reactive aldehyde. Western blot and real-time polymerase-chain reaction analyses and ATP-binding cassette (ABC) B1-functional assay revealed that, among three ABC transporters, ABCB1 was the most highly up-regulated by development of the CPT11 resistance, inferring a significant contribution of pregnane-X receptor-dependent signaling to the ABCB1 up-regulation. The combined treatment with inhibitors of AKR1C3 and ABCB1 potently sensitized the resistant cells to CPT11 and its active metabolite SN38. Taken together, our results suggest that combination of AKR1C3 and ABCB1 inhibitors is effective as adjuvant therapy to enhance CPT11 sensitivity of intractable colon cancer cells.


Subject(s)
Aldo-Keto Reductase Family 1 Member C3/metabolism , Colonic Neoplasms/metabolism , Drug Resistance, Neoplasm/drug effects , Irinotecan/pharmacology , ATP Binding Cassette Transporter, Subfamily B/metabolism , Aldehydes/metabolism , Cell Line, Tumor , Colonic Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Irinotecan/metabolism , Up-Regulation/drug effects
14.
PLoS One ; 15(8): e0228002, 2020.
Article in English | MEDLINE | ID: mdl-32764831

ABSTRACT

Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13-32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on irinotecan-based therapy in colon cancer. Using differentially expressing CTDSP1 cells, we demonstrated that CTDSP1 contributes to the irinotecan sensitivity by preventing topoI degradation. Retrospective analysis of patients receiving irinotecan with or without rabeprazole has shown the effects of CTDSP1 on irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.


Subject(s)
Colorectal Neoplasms/metabolism , DNA Topoisomerases, Type I/metabolism , Rabeprazole/metabolism , Cell Line, Tumor , Colonic Neoplasms/metabolism , Colorectal Neoplasms/physiopathology , DNA , DNA Topoisomerases, Type I/physiology , DNA-Activated Protein Kinase/metabolism , Drug Resistance/drug effects , Drug Resistance, Neoplasm/physiology , Humans , Irinotecan/metabolism , Irinotecan/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Phosphoprotein Phosphatases/metabolism , Proton Pump Inhibitors/pharmacology , Rabeprazole/pharmacology , Retrospective Studies , Topoisomerase I Inhibitors/pharmacology
15.
Sci Rep ; 10(1): 13486, 2020 08 10.
Article in English | MEDLINE | ID: mdl-32778670

ABSTRACT

Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5, DPYD, UGT1A1, ABCB1, and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients. One hundred and thirty-two patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy. Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, CYP3A4*1B, CYP3A4*18, CYP3A5*3, DPYD*5, UGT1A1*28, and UGT1A1*6 were 0.67, 0.43, 0.23, 0.27, 0.01, 0.02, 0.64, 0.19, 0.16, and 0.09, respectively. DPYD*2A and DPYD c.1774C > T variants were not detected in our study population. The ABCC2 c.3972C > T was significantly associated with grade 1-4 neutropenia (P < 0.012) at the first cycle. Patients carrying both UGT1A1*28 and *6 were significantly associated with severe neutropenia at the first (P < 0.001) and second (P = 0.017) cycles. In addition, patients carrying UG1A1*28 and *6 had significantly lower absolute neutrophil count (ANC) nadir at first (P < 0.001) and second (P = 0.001) cycles. This finding suggests that UGT1A1*28, *6, and ABCC2 c.3972C > T might be an important predictor for irinotecan-induced severe neutropenia.


Subject(s)
Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Irinotecan/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP-Binding Cassette Transporters/genetics , Adult , Aged , Alleles , Cytochrome P-450 CYP3A/genetics , Female , Gene Frequency/genetics , Genetic Variation/genetics , Genotype , Glucuronosyltransferase/genetics , Humans , Irinotecan/metabolism , Irinotecan/therapeutic use , Male , Membrane Transport Proteins/genetics , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Neutropenia/chemically induced , Polymorphism, Genetic/genetics , Thailand/epidemiology
16.
J Med Chem ; 63(10): 5421-5441, 2020 05 28.
Article in English | MEDLINE | ID: mdl-32352777

ABSTRACT

Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Drug Delivery Systems/methods , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Irinotecan/administration & dosage , Irinotecan/chemical synthesis , A549 Cells , Animals , Antineoplastic Agents/metabolism , Drug Design , HCT116 Cells , HSP90 Heat-Shock Proteins/metabolism , Humans , Irinotecan/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Xenograft Model Antitumor Assays/methods
17.
Bioorg Med Chem ; 28(7): 115377, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32081629

ABSTRACT

High-level of sialic acid (SA) expression on the surface of cancer cells is observed extremely common. Phenylboronic acids (PBAs) have a high affinity with SA. The cellular uptake efficiency could be enhanced by the strategy of introducing PBA fragments to the compounds. In this work, we synthesized five new probes with the Dicyanomethylene-4H-pyran (DCM) fluorophore, three of them conjugated with different phenylboronic acid fragments. By cellular uptake experiments, DLCB and DLAB showed enhanced cellular uptake abilities compared with DLN and DLO. These two effective phenylboronic acid fragments were then conjugated with SN-38 and the conjugates showed enhanced cellular uptake abilities by 3-fold or 7-fold compared with irinotecan. In summary, the strategy of introducing 4-carboxyphenylboronic acid and 3-amino-benzoxaborole groups shows great potential in drug delivery system. Moreover, the released linkers between boric acid and drugs deserve further studies.


Subject(s)
Antineoplastic Agents/metabolism , Boronic Acids/chemistry , Drug Design , Irinotecan/metabolism , Pyrans/chemistry , A549 Cells , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Transport , Cell Proliferation/drug effects , Fluorescent Dyes , Hep G2 Cells , Humans , Irinotecan/chemistry , Molecular Structure
18.
J Pharm Pharmacol ; 72(4): 575-582, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31975441

ABSTRACT

OBJECTIVES: Ezrin (Ezr), radixin (Rdx) and moesin (Msn) (ERM) proteins anchor other proteins to the cell membrane, serving to regulate their localization and function. Here, we examined whether ERM proteins functionally regulate breast cancer resistance protein (BCRP) and P-glycoprotein in cell lines derived from lung, intestinal and renal cancers. METHODS: ERM proteins were each silenced with appropriate siRNA. BCRP and P-gp functions were evaluated by means of efflux and uptake assays using 7-ethyl-10-hydroxycamptothecin (SN-38) and rhodamine123 (Rho123) as specific substrates, respectively, in non-small cell lung cancer HCC827 cells, intestinal cancer Caco-2 cells and renal cancer Caki-1 cells. KEY FINDINGS: In HCC827 cells, the efflux rates of SN-38 and Rho123 were significantly decreased by knockdown of Ezr or Msn, but not Rdx. However, BCRP function was unaffected by Ezr or Rdx knockdown in Caco-2 cells, which do not express Msn. In Caki-1 cells, Rdx knockdown increased the intracellular SN-38 concentration, while knockdown of Ezr or Msn had no effect. CONCLUSIONS: Our findings indicate that regulation of BCRP and P-gp functions by ERM proteins is organ-specific. Thus, if the appropriate ERM protein(s) are functionally suppressed, accumulation of BCRP or P-gp substrates in lung, intestine or kidney cancer tissue might be specifically increased.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Cytoskeletal Proteins/metabolism , Membrane Proteins/metabolism , Microfilament Proteins/metabolism , Neoplasm Proteins/metabolism , Caco-2 Cells/metabolism , Carcinoma, Non-Small-Cell Lung , Cell Line, Tumor , Cytoskeletal Proteins/genetics , Humans , Irinotecan/metabolism , Kidney Neoplasms/metabolism , Membrane Proteins/genetics , Microfilament Proteins/genetics , RNA, Messenger/metabolism , RNA, Small Interfering , Rhodamine 123/metabolism
19.
Mol Oncol ; 14(3): 645-656, 2020 03.
Article in English | MEDLINE | ID: mdl-31891442

ABSTRACT

Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell-surface antigen-2 (Trop-2) - a cell-surface glycoprotein highly expressed in many epithelial tumors - and delivers the active metabolite of irinotecan SN-38 to Trop-2-positive tumor cells. We evaluated Trop-2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiated EC cell lines and xenografts. Trop-2 expression was assessed in 143 formalin-fixed-paraffin-embedded tumors and seven primary tumor cell lines by immunohistochemistry and flow cytometry, respectively. Cell viability of primary tumor cell lines was assessed following exposure to SG, or control antibodies. Antibody-dependent cell cytotoxicity (ADCC) against Trop-2-positive and Trop-2-negative EC cell lines was measured in vitro using 4-h chromium release assays. A Trop-2-positive EC xenograft model was used to determine the in vivo activity of SG. Moderate-to-strong staining was detected in 84% (120/143) of EC samples, whereas 43% (3/7) of the primary EC cell lines tested overexpressed Trop-2. EC cell lines overexpressing Trop-2 were significantly more sensitive to SG compared to control ADC (P = 0.014 and P = 0.005). Both SG and the unconjugated parental antibody hRS7 mediated high ADCC against Trop-2-positive cell lines. Moreover, SG induced significant bystander killing of Trop-2-negative tumors cocultured with Trop-2-positive tumors. In the xenograft model, intravenous administration of SG twice weekly for three weeks was well tolerated and demonstrated impressive tumor growth inhibition against poorly differentiated, chemotherapy-resistant EC xenografts (P = 0.011). In summary, SG is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing Trop-2. These findings warrant future clinical trials.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antigens, Neoplasm/metabolism , Antineoplastic Agents/pharmacology , Camptothecin/analogs & derivatives , Carcinoma, Endometrioid/drug therapy , Cell Adhesion Molecules/metabolism , Cell Differentiation/drug effects , Endometrial Neoplasms/drug therapy , Immunoconjugates/pharmacology , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Antibody-Dependent Cell Cytotoxicity , Antineoplastic Agents/administration & dosage , Camptothecin/administration & dosage , Camptothecin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Immunoconjugates/administration & dosage , Immunohistochemistry , Irinotecan/metabolism , Mice , Mice, SCID , Tissue Array Analysis , Xenograft Model Antitumor Assays
20.
Xenobiotica ; 50(1): 64-76, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31092094

ABSTRACT

The role that the phase-II reaction, glucuronidation, plays in the biotransformation of endo and xenobiotics is discussed with particular emphasis given to the UGT1A1 isoenzyme. This individual isoenzyme is responsible for both the mono and di-glucuronidation of bilirubin together with the glucuronidation of a number of xenobiotics of clinical interest (irinotecan, belinostat, atazanavir, pegvisomant).The review then discusses the roles that the various allelic variants of the UGT1A1 gene play in bilirubin metabolism and in particular how these allelic variants are involved in the clinical manifestation of the diseases of GS, CN1 and CN2.The review concludes with the roles that the UGT1A1*28 and UGT1A1*6 alleles play in adverse drug reactions (decreased glucuronidation of irinotecan, belinostat, atazanavir, pegvisomant) leading to increased exposure, reduced clearance and neutropenia (irinotecan, belinostat), increased risk for jaundice and hyperbilirubinaemia (atazanavir) and liver toxicity (pegvisomant) before discussing the future role of UGT1A1 in personalised medicine.


Subject(s)
Glucuronosyltransferase/genetics , Alleles , Bilirubin , Genotype , Glucuronosyltransferase/metabolism , Humans , Hydroxamic Acids/metabolism , Hyperbilirubinemia/metabolism , Irinotecan/metabolism , Sulfonamides/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...