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1.
Molecules ; 29(11)2024 May 24.
Article in English | MEDLINE | ID: mdl-38893358

ABSTRACT

Pseudoginsenoside DQ (PDQ), an ocotillol-type ginsenoside, is synthesized with protopanaxadiol through oxidative cyclization. PDQ exhibits good anti-arrhythmia activity. However, the inhibitory effect of PDQ on the cytochrome 450 (CYP450) enzymes and major drug transporters is still unclear. Inhibition of CYP450 and drug transporters may affect the efficacy of the drugs being used together with PDQ. These potential drug-drug interactions (DDIs) are essential for the clinical usage of drugs. In this study, we investigated the inhibitory effect of PDQ on seven CYP450 enzymes and seven drug transporters with in vitro models. PDQ has a significant inhibitory effect on CYP2C19 and P-glycoprotein (P-gp) with a half-inhibitory concentration (IC50) of 0.698 and 0.41 µM, respectively. The inhibition of CYP3A4 and breast cancer-resistant protein (BCRP) is less potent, with IC50 equal to 2.02-6.79 and 1.08 µM, respectively.


Subject(s)
Cytochrome P-450 Enzyme System , Drug Interactions , Ginsenosides , Humans , Ginsenosides/pharmacology , Ginsenosides/chemistry , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP2C19/metabolism , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors
2.
Int J Mol Sci ; 25(11)2024 May 30.
Article in English | MEDLINE | ID: mdl-38892219

ABSTRACT

Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 µM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 µM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.


Subject(s)
Anoctamin-1 , Antineoplastic Agents , Hemin , Neoplasm Proteins , Prostatic Neoplasms , Humans , Male , Anoctamin-1/metabolism , Anoctamin-1/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Hemin/pharmacology , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , PC-3 Cells , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology
3.
Cell Calcium ; 121: 102905, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38788257

ABSTRACT

TMEM16 proteins, also known as anoctamins, are a family of ten membrane proteins with various tissue expression and subcellular localization. TMEM16A (anoctamin 1) is a plasma membrane protein that acts as a calcium-activated chloride channel. It is expressed in many types of epithelial cells, smooth muscle cells and some neurons. In airway epithelial cells, TMEM16A expression is particularly enhanced by inflammatory stimuli that also promote goblet cell metaplasia and mucus hypersecretion. Therefore, pharmacological modulation of TMEM16A could be beneficial to improve mucociliary clearance in chronic obstructive respiratory diseases. However, the correct approach to modulate TMEM16A activity (activation or inhibition) is still debated. Pharmacological inhibitors of TMEM16A could also be useful as anti-hypertensive agents given the TMEM16A role in smooth muscle contraction. In contrast to TMEM16A, TMEM16F (anoctamin 6) behaves as a calcium-activated phospholipid scramblase, responsible for the externalization of phosphatidylserine on cell surface. Inhibitors of TMEM16F could be useful as anti-coagulants and anti-viral agents. The role of other anoctamins as therapeutic targets is still unclear since their physiological role is still to be defined.


Subject(s)
Anoctamin-1 , Humans , Animals , Anoctamin-1/metabolism , Anoctamin-1/antagonists & inhibitors , Anoctamins/metabolism , Chloride Channels/metabolism , Chloride Channels/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Phospholipid Transfer Proteins/metabolism , Phospholipid Transfer Proteins/antagonists & inhibitors
4.
J Clin Invest ; 134(13)2024 May 21.
Article in English | MEDLINE | ID: mdl-38771655

ABSTRACT

Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.


Subject(s)
Histones , Radiation Tolerance , Humans , Animals , Mice , Radiation Tolerance/drug effects , Radiation Tolerance/genetics , Histones/metabolism , Histones/genetics , Cell Line, Tumor , Xenograft Model Antitumor Assays , DNA Repair/drug effects , Glioma/radiotherapy , Glioma/pathology , Glioma/genetics , Glioma/metabolism , Glioma/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Brain Neoplasms/metabolism , Brain Neoplasms/drug therapy , Radiation-Sensitizing Agents/pharmacology , Transcription Factors/genetics , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , DNA Damage , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Bromodomain Containing Proteins , Proteins
5.
Clin Pharmacol Drug Dev ; 13(7): 755-769, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38752475

ABSTRACT

Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Cytochrome P-450 Enzyme System , Drug Interactions , Humans , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 Enzyme System/drug effects , Female , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Male , Adult , Bupropion/pharmacology , Bupropion/pharmacokinetics , Sulfonamides/pharmacology , Middle Aged , Rosuvastatin Calcium/pharmacology , Rosuvastatin Calcium/pharmacokinetics , Flurbiprofen/pharmacology , Flurbiprofen/pharmacokinetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Organic Anion Transporters/metabolism , Organic Anion Transporters/antagonists & inhibitors , Carbamates/pharmacology , Midazolam/pharmacokinetics , Midazolam/pharmacology , Young Adult , Piperidines/pharmacology , Piperidines/pharmacokinetics
6.
Future Med Chem ; 16(8): 723-735, 2024.
Article in English | MEDLINE | ID: mdl-38573062

ABSTRACT

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.


[Box: see text].


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Antineoplastic Agents , Neoplasm Proteins , Oxadiazoles , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Cell Proliferation/drug effects , Molecular Structure , Cell Line, Tumor , Drug Screening Assays, Antitumor
7.
Photochem Photobiol Sci ; 23(6): 1067-1075, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38625651

ABSTRACT

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Anthracenes , Colorectal Neoplasms , Febuxostat , Neoplasm Proteins , Perylene , Photochemotherapy , Photosensitizing Agents , Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Anthracenes/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Perylene/analogs & derivatives , Perylene/pharmacology , Febuxostat/pharmacology , Febuxostat/therapeutic use , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , HEK293 Cells , Cell Survival/drug effects , HT29 Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
8.
Expert Opin Ther Targets ; 28(4): 259-271, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38653737

ABSTRACT

INTRODUCTION: Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers. AREAS COVERED: In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment. EXPERT OPINION: Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.


Subject(s)
Antineoplastic Agents , Hematologic Neoplasms , Molecular Targeted Therapy , Protein Tyrosine Phosphatases , Signal Transduction , Humans , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/metabolism , Hematologic Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Signal Transduction/drug effects , Enzyme Inhibitors/pharmacology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Drug Development , Membrane Proteins , Cell Cycle Proteins
9.
Comput Biol Chem ; 110: 108039, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38471352

ABSTRACT

Hepatocellular carcinoma (HCC) persists to be one of the most devastating and deadliest malignancies globally. Recent research into the molecular signaling networks entailed in many malignancies has given some prominent insights that can be leveraged to create molecular therapeutics for combating HCC. Therefore, in the current communication, an in-silico drug repurposing approach has been employed to target the function of PTP4A3/PRL-3 protein in HCC using antidepressants: Fluoxetine hydrochloride, Citalopram, Amitriptyline, Imipramine, and Escitalopram oxalate as the desired ligands. The density function theory (DFT) and chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters for the chosen ligands were evaluated to comprehend the pharmacokinetics, drug-likeness properties, and bioreactivity of the ligands. The precise interaction mechanism was explored using computational methods such as molecular docking and molecular dynamics (MD) simulation studies to assess the inhibitory effect and the stability of the interactions against the protein of interest. Escitalopram oxalate exhibited a comparatively significant docking score (-7.4 kcal/mol) compared to the control JMS-053 (-6.8 kcal/mol) against the PRL-3 protein. The 2D interaction plots exhibited an array of hydrophobic and hydrogen bond interactions. The findings of the ADMET forecast confirmed that it adheres to Lipinski's rule of five with no violations, and DFT analysis revealed a HOMO-LUMO energy gap of -0.26778 ev, demonstrating better reactivity than the control molecule. The docked complexes were subjected to MD studies (100 ns) showing stable interactions. Considering all the findings, it can be concluded that Escitalopram oxalate and related therapeutics can act as potential pharmacological candidates for targeting the activity of PTP4A3/PRL-3 in HCC.


Subject(s)
Antidepressive Agents , Carcinoma, Hepatocellular , Escitalopram , Liver Neoplasms , Molecular Docking Simulation , Protein Tyrosine Phosphatases , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/chemistry , Escitalopram/chemistry , Escitalopram/pharmacology , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Molecular Dynamics Simulation , Oxalates/chemistry , Oxalates/metabolism , Density Functional Theory , Molecular Structure , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
10.
J Clin Invest ; 134(10)2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38530357

ABSTRACT

Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-ß signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.


Subject(s)
5'-Nucleotidase , Proteolysis , Triple Negative Breast Neoplasms , Animals , Female , Humans , Mice , 5'-Nucleotidase/genetics , 5'-Nucleotidase/immunology , 5'-Nucleotidase/antagonists & inhibitors , Cell Line, Tumor , GPI-Linked Proteins/immunology , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/antagonists & inhibitors , Neoplasm Proteins/immunology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Ubiquitination , Ubiquitin-Specific Proteases
11.
Ann Hematol ; 103(7): 2405-2417, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38538975

ABSTRACT

Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.


Subject(s)
Ferroptosis , Heme Oxygenase-1 , Multiple Myeloma , NF-E2-Related Factor 2 , Signal Transduction , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/metabolism , Ferroptosis/drug effects , Humans , NF-E2-Related Factor 2/metabolism , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Cell Line, Tumor , Signal Transduction/drug effects , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/genetics , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Histocompatibility Antigens
12.
Talanta ; 274: 125987, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38552478

ABSTRACT

Multidrug resistance (MDR) is a dominant challenge in cancer chemotherapy failure. The over-expression of breast cancer resistance protein (BCRP) in tumorous cells, along with its extensive substrate profile, is a leading cause of tumor MDR. Herein, on the basis of styrene maleic acid (SMA) polymer membrane protein stabilization strategy and surface plasmon resonance (SPR) biosensor, a novel high-throughput screening (HTS) system for BCRP inhibitors has been established. Firstly, LLC-PK1 and LLC-PK1/BCRP cell membranes were co-incubated with SMA polymers to construct SMA lipid particles (SMALPs). PK1-SMALPs were thus immobilized in channel 1 of the L1 chip as the reference channel, and BCRP-SMALPs were immobilized in channel 2 as the detection channel to establish the BCRP-SMALPs-SPR screening system. The methodological investigation demonstrated that the screening system was highly specific and stable. Three active compounds were screened out from 26 natural products and their affinity constants with BCRP were determined. The KD of xanthotoxin, bergapten, and naringenin were 5.14 µM, 4.57 µM, and 3.72 µM, respectively. The in vitro cell verification experiments demonstrated that xanthotoxin, bergapten, and naringenin all significantly increased the sensitivity of LLC-PK1/BCRP cells to mitoxantrone with possessing reversal BCRP-mediated MDR activity. Collectively, the developed BCRP-SMALPs-SPR screening system in this study has the advantages of rapidity, efficiency, and specificity, providing a novel strategy for the in-depth screening of BCRP inhibitors with less side effects and higher efficacy.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Maleates , Neoplasm Proteins , Surface Plasmon Resonance , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Surface Plasmon Resonance/methods , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasm Proteins/analysis , Humans , Maleates/chemistry , Maleates/pharmacology , Animals , High-Throughput Screening Assays/methods , Swine , Polystyrenes/chemistry , Biosensing Techniques/methods
13.
J Pharmacol Exp Ther ; 390(2): 162-173, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-38296646

ABSTRACT

We recently showed that riboflavin is a selected substrate of breast cancer resistance protein (BCRP) over P-glycoprotein (P-gp) and demonstrated its prediction performance in preclinical drug-drug interaction (DDI) studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin toward other major drug transporters using established transfected cell systems. Riboflavin is a substrate for organic anion transporter (OAT)1, OAT3, and multidrug and toxin extrusion protein (MATE)2-K, with uptake ratios ranging from 2.69 to 11.6, but riboflavin is not a substrate of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)2, and MATE1. The effects of BMS-986371, a potent in vitro inhibitor of BCRP (IC 50 0.40 µM), on the pharmacokinetics of riboflavin, isobutyryl carnitine, and arginine were then examined in healthy male adults (N = 14 or 16) after oral administration of methotrexate (MTX) (7.5 mg) and enteric-coated (EC) sulfasalazine (SSZ) (1000 mg) alone or in combination with BMS-986371 (150 mg). Oral administration of BMS-986371 increased the area under the plasma concentration-time curves (AUCs) of rosuvastatin and immediate-release (IR) SSZ to 1.38- and 1.51-fold, respectively, and significantly increased AUC(0-4h), AUC(0-24h), and C max of riboflavin by 1.25-, 1.14-, and 1.11-fold (P-values of 0.003, 0.009, and 0.025, respectively) compared with the MTX/SSZ EC alone group. In contrast, BMS-986371 did not significantly influence the AUC(0-24h) and C max values of isobutyryl carnitine and arginine (0.96- to 1.07-fold, respectively; P > 0.05). Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development. SIGNIFICANCE STATEMENT: Endogenous compounds that serve as biomarkers for clinical inhibition of breast cancer resistance protein (BCRP) are not currently available. This study provides the initial evidence that riboflavin is a promising BCRP biomarker in humans. For the first time, the value of leveraging the substrate of BCRP with acceptable prediction performance in clinical studies is shown. Additional clinical investigations with known BCRP inhibitors are needed to fully validate and showcase the utility of this biomarker.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Neoplasm Proteins , Riboflavin , Humans , Riboflavin/pharmacokinetics , Riboflavin/metabolism , Riboflavin/blood , Pilot Projects , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Adult , Male , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Biomarkers/blood , Biomarkers/metabolism , Healthy Volunteers , Young Adult , Methotrexate/pharmacokinetics , Methotrexate/pharmacology , Methotrexate/metabolism , Methotrexate/blood , Middle Aged
14.
Int J Mol Sci ; 25(2)2024 Jan 20.
Article in English | MEDLINE | ID: mdl-38279296

ABSTRACT

Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.


Subject(s)
Biomarkers , Breast Neoplasms , Exosomes , MicroRNAs , Female , Humans , Biomarkers/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Transformation, Neoplastic/metabolism , Exosomes/genetics , Exosomes/metabolism , MicroRNAs/metabolism , Neoplasm Proteins/antagonists & inhibitors
15.
J Med Chem ; 66(4): 2804-2831, 2023 02 23.
Article in English | MEDLINE | ID: mdl-36780419

ABSTRACT

ABCB1 and ABCG2 are the important ATP-binding cassette (ABC) transporters associated with multidrug resistance (MDR). Herein, we designed a series of imidazo[1,2-a]pyridine derivatives as dual-target inhibitors of ABCB1 and ABCG2 through the scaffold hopping strategy. Compound Y22 displayed potential efflux function inhibitory toward both ABCB1 and ABCG2 (reversal fold: ABCB1 = 8.35 and ABCG2 = 2.71) without obvious cytotoxicity. Y22 also enhanced the potency of antiproliferative drugs in vitro. Mechanistic studies demonstrated that Y22 slightly suppressed ATPase activity but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the antiproliferative activity of adriamycin in vivo by restoring the sensitivity of resistant cells. Thus, Y22 may be effective clinically in combination with common chemotherapy agents. In summary, Y22 is a potential dual-target inhibitor that reverses MDR by blocking the efflux function of ABCB1 and ABCG2.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 2 , Antineoplastic Agents , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Neoplasm Proteins , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Pyridines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 2/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Humans
16.
Proc Natl Acad Sci U S A ; 119(30): e2120339119, 2022 07 26.
Article in English | MEDLINE | ID: mdl-35857873

ABSTRACT

During translation initiation, eIF4G1 dynamically interacts with eIF4E and eIF1. While the role of eIF4E-eIF4G1 is well established, the regulatory functions of eIF4G1-eIF1 are poorly understood. Here, we report the identification of the eIF4G1-eIF1 inhibitors i14G1-10 and i14G1-12. i14G1s directly bind eIF4G1 and inhibit translation in vitro and in the cell, and their effects on translation are dependent on eIF4G1 levels. Translatome analyses revealed that i14G1s mimic eIF1 and eIF4G1 perturbations on the stringency of start codon selection and the opposing roles of eIF1-eIF4G1 in scanning-dependent and scanning-independent short 5' untranslated region (UTR) translation. Remarkably, i14G1s activate ER/unfolded protein response (UPR) stress-response genes via enhanced ribosome loading, elevated 5'UTR translation at near-cognate AUGs, and unexpected concomitant up-regulation of coding-region translation. These effects are, at least in part, independent of eIF2α-phosphorylation. Interestingly, eIF4G1-eIF1 interaction itself is negatively regulated by ER stress and mTOR inhibition. Thus, i14G1s uncover an unknown mechanism of ER/UPR translational stress response and are valuable research tools and potential drugs against diseases exhibiting dysregulated translation.


Subject(s)
Endoplasmic Reticulum Stress , Eukaryotic Initiation Factor-2 , Eukaryotic Initiation Factor-4G , Eukaryotic Initiation Factors , Neoplasm Proteins , Nerve Tissue Proteins , Unfolded Protein Response , Animals , Codon, Initiator , Endoplasmic Reticulum Stress/genetics , Eukaryotic Initiation Factor-2/metabolism , Eukaryotic Initiation Factor-4G/antagonists & inhibitors , Eukaryotic Initiation Factor-4G/metabolism , Eukaryotic Initiation Factors/antagonists & inhibitors , Eukaryotic Initiation Factors/metabolism , Humans , Mice , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Phosphorylation , Protein Biosynthesis , Unfolded Protein Response/genetics
17.
J Med Chem ; 65(10): 7231-7245, 2022 05 26.
Article in English | MEDLINE | ID: mdl-35522528

ABSTRACT

MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.


Subject(s)
Antigens, Neoplasm , Neoplasm Proteins , Neoplasms , Antigens, Neoplasm/chemistry , DNA Damage , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Male , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/chemistry , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Structure-Activity Relationship , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
18.
Eur J Med Chem ; 237: 114346, 2022 Jul 05.
Article in English | MEDLINE | ID: mdl-35483322

ABSTRACT

The primary source of failure of cancer therapies is multidrug resistance (MDR), which can be caused by different mechanisms, including the overexpression of ABC transporters in cancer cells. Among the 48 human ABC proteins, the breast cancer resistance protein (BCRP/ABCG2) has been described as a pivotal player in cancer resistance. The use of functional inhibitors and expression modulators is a promising strategy to overcome the MDR caused by ABCG2. Despite the lack of clinical trials using ABCG2 inhibitors, many compounds have already been discovered. This review presents an overview about various ABCG2 inhibitors that have been identified, discussing some chemical aspects and the main experimental methods used to identify and characterize the mechanisms of new inhibitors. In addition, some biological requirements to pursue preclinical tests are described. Finally, we discuss the potential use of ABCG2 inhibitors in cancer stem cells (CSC) for improving the objective response rate and the mechanism of ABCG2 modulators at transcriptional and protein expression levels.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Neoplasm Proteins , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Humans , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/drug effects
19.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: mdl-35208952

ABSTRACT

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.


Subject(s)
Antineoplastic Agents , Chalcones , Cyclooxygenase 2 Inhibitors , Neoplasm Proteins , Neoplasms , Protein Kinase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/chemistry , Chalcones/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , Humans , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
20.
Blood ; 139(8): 1160-1176, 2022 02 24.
Article in English | MEDLINE | ID: mdl-35201323

ABSTRACT

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients' primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients' primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.


Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Antineoplastic Agents, Immunological/pharmacology , Bone Marrow Cells , Membrane Glycoproteins/antagonists & inhibitors , Multiple Myeloma , Neoplasm Proteins/antagonists & inhibitors , ADP-ribosyl Cyclase 1/metabolism , Animals , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Cell Line, Tumor , HEK293 Cells , Humans , Membrane Glycoproteins/metabolism , Mice, Transgenic , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasm Proteins/metabolism , Xenograft Model Antitumor Assays
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