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1.
J Immunol ; 209(1): 171-179, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35725272

RESUMO

Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during cancer chemotherapy. We previously demonstrated that topotecan (TPT), a topoisomerase I inhibitor, induces DAMP secretion from cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in cancer cells is yet to be elucidated. Here, we identified RPL15, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited preribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. TPT inhibits RPL15-RPL4 interactions and decreases RPL4 stability, which is recovered by CDK12 activity. RPL15 knockdown induced DAMP secretion and increased the CTL population but decreased the regulatory T cell population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.


Assuntos
Neoplasias , Topotecan , Animais , Camundongos , Neoplasias/tratamento farmacológico , Proteínas Ribossômicas , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia , Topotecan/uso terapêutico
2.
FASEB J ; 36(6): e22294, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35579890

RESUMO

Excessive neuroinflammation and neuronal loss contribute to mechanisms of spinal cord injury (SCI). Accumulating evidence has suggested that topoisomerase 1 (Top1) inhibition can suppress exacerbated immune responses and protect against lethal inflammation. Pyroptosis is a recently identified pro-inflammatory programmed mode of cell death. However, the effects and underlying mechanisms of Top1 inhibition in SCI remains unclear. Locomotor functional recovery in mice was evaluated through Basso Mouse Scale (BMS). Neuronal loss was evaluated by immunochemistry staining of NeuN. Pyroptosis was determined by immunofluorescence staining, western blot, flow cytometry, cell viability, and cytotoxicity assays. In the present study, we estimated the effects of chemical inhibition of Top1 in an SCI model. Administration of Top1 inhibitor camptothecin (CPT) to mice significantly improved locomotor functional recovery after SCI. Moreover, CPT reduced Top1 level, inhibited nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation and pyroptosis, attenuated proinflammatory cytokines levels, diminished the number of neutrophil and neuronal loss in mice. Furthermore, CPT in oxygen-glucose deprivation neurons down-regulated Top1 level, attenuated NLRP3 inflammasome activation, and suppressed pyroptosis and inflammatory response. Together, our findings indicate that inhibition of Top1 with CPT can inhibit pyroptosis, control neuroinflammation, and improve functional recovery after SCI.


Assuntos
Traumatismos da Medula Espinal , Inibidores da Topoisomerase I , Animais , Camptotecina/farmacologia , Inflamassomos/metabolismo , Inflamação/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Inibidores da Topoisomerase I/farmacologia
3.
Eur J Med Chem ; 238: 114465, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35635947

RESUMO

With the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 µM against A549 and 3.02-10.91 µM in the other tested cancer cell lines. Gratifyingly, 11g displayed 43-fold higher selectivity towards A549 cancer cells as compared to the non-cancer cells. Subsequently, conjugate 12g also demonstrated significant cytotoxicity against SK-MEL-28 cells. Basing the in vitro cytotoxicity results, SAR was established. Later, the conjugates 11g and 12g were further evaluated for their apoptosis-inducing ability, which was quantified by flow cytometric analysis, DNA-binding, Topo I inhibitory activity and IC50 value calculation. Molecular modeling studies provided profound insights about the binding nature of these compounds with DNA-Topo I complex. In silico ADME/T and prediction studies corroborated the drug-likeness of the two investigated compounds. TOPKAT toxicity profiling studies demonstrated the compounds' safety in many animal models with a minimal toxicological profile. Encouraging results obtained from in vitro and in silico studies could put this series of conjugates at the forefront of cancer drug discovery.


Assuntos
Antineoplásicos , Inibidores da Topoisomerase I , Animais , Antineoplásicos/química , Azepinas , Linhagem Celular Tumoral , Proliferação de Células , DNA/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Pirróis , Relação Estrutura-Atividade , Tiazolidinas , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia
4.
Bioorg Chem ; 126: 105870, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35636125

RESUMO

Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.


Assuntos
Antineoplásicos , Quinolinas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Quinase 2 Dependente de Ciclina , Células HCT116 , Humanos , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia
5.
EMBO Rep ; 23(7): e54499, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35593064

RESUMO

Targeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Our in silico drug screening reveals topoisomerase 1 (TOP1) inhibitors as promising drug candidates for microglial modulation. We show that TOP1 is highly expressed in neuroinflammatory conditions, and TOP1 inhibition using camptothecin (CPT) and its FDA-approved analog topotecan (TPT) reduces inflammatory responses in microglia/macrophages and ameliorates neuroinflammation in vivo. Transcriptomic analyses of sorted microglia from LPS-challenged mice reveal an altered transcriptional phenotype following TPT treatment. To target myeloid cells, we design a nanosystem using ß-glucan-coated DNA origami (MyloGami) loaded with TPT (TopoGami). MyloGami shows enhanced specificity to myeloid cells while preventing the degradation of the DNA origami scaffold. Myeloid-specific TOP1 inhibition using TopoGami significantly suppresses the inflammatory response in microglia and mitigates MS-like disease progression. Our findings suggest that TOP1 inhibition in myeloid cells represents a therapeutic strategy for neuroinflammatory diseases and that the myeloid-specific nanosystems we designed may also benefit the treatment of other diseases with dysfunctional myeloid cells.


Assuntos
Doenças Neuroinflamatórias , Inibidores da Topoisomerase I , Animais , DNA , Macrófagos , Camundongos , Inibidores da Topoisomerase I/farmacologia , Topotecan/farmacologia
6.
J Med Chem ; 65(11): 8040-8061, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35612499

RESUMO

Calothrixin A (CAA) is a dual Topo I and II inhibitor but exhibits poor antiproliferative activities and water solubility. Herein, a library of novel CAA analogues was synthesized. Among them, compound F16 exhibited superior water solubility (>5 mg/mL) as compared to CAA (<5 µg/mL). The mechanism of action studies confirmed that F16 acted as a dual Topo I and II poison. Furthermore, F16 displayed potent antiproliferative activities against high Topo I and II expression cell lines A375 and HCT116, with IC50 values of 20 and 50 nM, respectively. In xenograft models, F16 reduced the tumor growth at a dose of 10 or 20 mg/kg without apparent effect on the mouse weight, while the clinically used Topo II inhibitor VP-16 dramatically reduced the mouse weight. Collectively, our data demonstrated that F16 could be a promising lead for the development of novel dual Topo I and II antitumor agents.


Assuntos
Antineoplásicos , Produtos Biológicos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos , Camundongos , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Inibidores da Topoisomerase II/farmacologia , Água/metabolismo
7.
J Inorg Biochem ; 232: 111816, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35405490

RESUMO

Topoisomerase (Topo) accelerates cell growth and division, and has been a theoretical target for anti-cancer drugs for decades. A series of pyridoxal thiosemicarbazone (PLT) ligands were designed and synthesized, and the dependence of their antiproliferative activity on copper was investigated. The insertion of N-cyclohexyl-2-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methylene)-N-methylhydrazinecarbothioamide hydrochloride (compound 9) and Chlorido(N-cyclohexyl-2-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methylene)-N-methylhydrazinecarbothioamide hydrochloride-O,N,S)­copper(II) nitrate (9-Cu complex) into Topo-I and Topo-II prevented uncoiling of DNA through hydrogen bonds and intermolecular forces. The combination of PLT derivatives and copper gluconate (CuGlu) improved their anti-tumour activity against a cell line with high expression of topoisomerase (SK-BR-3). The non-linear regression equations of the inhibitory activity and anti-tumour activity of Topo-I and Topo-IIɑ in SK-BR-3 cells had R2 values of 0.93 and 0.94, respectively. In addition to lipophilicity, inhibition of topoisomerase also affected the activity of PLT ligands by coordinating with copper ions. At the cellular level, PLTs and CuGlu penetrate the cell membrane to form metabolites in the cell, thus selectively inhibiting the activity of Topo-I and Topo-IIɑ, and ultimately inhibiting cell division. These findings will inform the design of future anti-cancer thiosemicarbazone drugs.


Assuntos
Antineoplásicos , Neoplasias , Tiossemicarbazonas , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/química , Divisão Celular , Cobre/química , DNA Topoisomerases Tipo II/metabolismo , Humanos , Íons , Ligantes , Neoplasias/tratamento farmacológico , Piridoxal/análogos & derivados , Piridoxal/farmacologia , Tiossemicarbazonas/química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/química
8.
Eur J Med Chem ; 236: 114304, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35413618

RESUMO

Topoisomerase IB (Top1), a subcategory of DNA topoisomerase enzymes is expressed much higher in several tumor cells. Therefore, modulating the activity of Top1 in tumor cells to prevent DNA replication and subsequent cell division made it an important drug target for anticancer therapy. FDA-approved camptothecin (CPT) derivatives topotecan and irinotecan exert anticancer activity through stabilization of enzyme-mediated DNA cleavage complex forming a ternary complex between DNA-Top1-drug. However, CPT derivatives suffer from several limitations which prompted interest in the development of 'non-camptothecin' Top1 poisons as anticancer agents. This review aims to provide chronological development of different classes of Top1 poisons from both natural and synthetic sources through strategic structure-activity relationship (SAR) analysis with insight into the important structural features in different chemotypes that imparted Top1 inhibition along with the understanding of the structural basis of inhibition. This review also provides a snapshot of the application of Top1 poisons in various combination therapies in recent times. We believe such a comprehensive review is going to be beneficial for the medicinal chemistry community to design efficient drug development strategies using existing knowledge.


Assuntos
Antineoplásicos , Venenos , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina , DNA Topoisomerases Tipo I/metabolismo , Irinotecano , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia
9.
Bioorg Chem ; 123: 105789, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35429714

RESUMO

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that repairs DNA lesions caused by the trapping of DNA topoisomerase IB (TOP1)-DNA break-associated crosslinks. TDP1 inhibitors have synergistic effect with TOP1 inhibitors in cancer cells and can overcome cancer cell resistance to TOP1 inhibitors. Here, we report the synthesis of 11-aminoalkoxy substituted benzophenanthridine derivatives as selective TDP1 inhibitors and show that six compounds 14, 16, 18, 20, 25 and 27 exhibit high TDP1 inhibition potency. The most potent TDP1 inhibitor 14 (IC50 = 1.7 ±â€¯0.24 µM) induces cellular TDP1cc formation and shows synergistic effect with topotecan in four human cancer cell lines MCF-7, A549, H460 and HepG2.


Assuntos
Diester Fosfórico Hidrolases , Inibidores da Topoisomerase I , Benzofenantridinas , DNA Topoisomerases Tipo I/metabolismo , Humanos , Diester Fosfórico Hidrolases/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/farmacologia
10.
Biochem Pharmacol ; 200: 115049, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35469784

RESUMO

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC50 values of 0.03, 0.09, 0.22, and 0.32 µM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human hepatoma cells and immortalized normal human liver cell line (IC50(L-02)/IC50(HepG2) = 113.20; IC50(L-02)/IC50(Hep3B) = 85.60) than topotecan (IC50(L-02)/IC50(HepG2) = 9.45; IC50(L-02)/IC50(Hep3B) = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of topotecan. Meanwhile, XJS-11 could attenuate the tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the camptothecin-derived drug candidate.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Ovarianas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cinamatos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/farmacologia
11.
Mol Cancer Ther ; 21(7): 1090-1102, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35439320

RESUMO

Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.


Assuntos
DNA Topoisomerases Tipo I , Neoplasias , Inibidores da Topoisomerase I , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camptotecina/análogos & derivados , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores da Topoisomerase I/farmacologia
12.
Expert Opin Drug Discov ; 17(6): 581-601, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35321631

RESUMO

INTRODUCTION: Cancer has been identified as one of the leading causes of death worldwide. The biological target of some anticancer agents is topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA. The synthesis of new compounds with antiproliferative effect and behaving as topoisomerase I inhibitors has become an active field of research. Depending on their mechanism of inhibition, they can be classified as catalytic inhibitors or poisons. AREAS COVERED: This review article summarizes the state of the art for the development of selective topoisomerase I inhibitors. Collected compounds showed inhibition of the enzyme, highlighting those approved for clinical use, the combination therapies developed, as well as related drawbacks and future focus. EXPERT OPINION: Research related to topoisomerase I inhibitors in cancer therapy started with camptothecin (CPT). This compound was first selected as a good anticancer agent and then topoisomerase I was identified as its therapeutic target. Derivatives of CPT irinotecan, topotecan, and belotecan are the only clinically approved inhibitors. Currently, their limitations are being addressed by different stretegies. Future studies should focus not only on developing other active molecules but also on improving the bioavailability and pharmacokinetics of potent synthetic derivatives.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/uso terapêutico , Inibidores Enzimáticos/farmacologia , Humanos , Irinotecano/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/farmacocinética , Topotecan/uso terapêutico
13.
Mol Cancer Ther ; 21(4): 635-646, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35149548

RESUMO

B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3-expressing cancer cells, but not that of B7-H3-negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high-B7-H3 tumor xenograft models, including various tumor types of high-B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3-expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3-expressing solid tumors in a clinical setting.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Imunoconjugados/uso terapêutico , Macaca fascicularis , Camundongos , Neoplasias/patologia , Ratos , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico
14.
PLoS One ; 17(2): e0263463, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35143532

RESUMO

Neuroblastomas are one of the most common types of solid tumors in infants and children and are responsible for approximately 15% of childhood cancer deaths. Neuroblastomas rarely have mutations in p53, with less than 2% of NB containing mutations in p53, compared to up to 60% for other tumor classes. Previous studies on the therapeutic combination of a DNA damaging agent and checkpoint kinase 1 (Chk1) inhibitor have shown that DNA damage-induced cell cycle arrest can be specifically abrogated in p53-defective tumors. However, some p53-wildtype tumors have also been shown to be sensitive to this therapeutic combination, suggesting that these cells have other defects in the p53 response that can be exploited for therapeutic purposes. In the current study, we investigated the response to the combination of a DNA damaging agent (SN38) and a Chk1 inhibitor (UCN-01) of four p53-wildtype neuroblastoma cell lines: SK-N-SH, SH-SY5Y, SK-N-AS, and Lan-5. When the cells were treated with concentrations of SN38 ranging from 0-30 ng/ml, all four cell lines accumulated p53 which was phosphorylated on serines 15 and 20. However, only the SK-N-SH were found to activate p21waf1 and repress cyclin B. In order to assess sensitivity to UCN-01-mediated abrogation of cell cycle arrest, cell were treated with 10 ng/ml SN38 for 24 h, followed by 25 nM UCN-01 for 6 and 24 h. The SK-N-SH showed no sensitivity to UCN-01 treatment whereas the SH-SY5Y, SK-N-AS, and Lan-5 abrogated G2 arrest within 24 h. Our recent studies revealed that cells that are sensitive to checkpoint abrogation lack p53 dimers and tetramers, so we analyzed the oligomerization status of p53 in all four cell lines using glutaraldehyde crosslinking. The SK-N-SH cells possessed levels of p53 dimers and tetramers similar to what has previously been reported in p53-wildtype MCF10A cells. The SH-SY5Y, SK-N-AS, and Lan-5 however, had extremely low to undetectable levels of dimers and tetramers. Our study also showed no cytoplasmic accumulation of p53 in these cells contrary to some previous reports. The results of this study suggest that oligomerization status may serve as an indicator of sensitivity of p53-wildtype tumors to the therapeutic combination of DNA damaging agent and Chk1 inhibitor.


Assuntos
Antineoplásicos/farmacologia , Genes p53 , Irinotecano/farmacologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Estaurosporina/análogos & derivados , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , Humanos , Irinotecano/uso terapêutico , Estaurosporina/farmacologia , Estaurosporina/uso terapêutico , Inibidores da Topoisomerase I/uso terapêutico
15.
Chem Biol Interact ; 351: 109758, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34826397

RESUMO

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC50 values range from 55.0 to 77.0 µg/ml, with 3m (IC50 55.75 µg/ml) being equipotent with amphotericin B (IC50 50.0 µg/ml, used as standard). The most active compound 3m, is metabolically stable in rat liver microsomes. Furthermore, the molecules are highly specific against leishmania as shown by their weak antibacterial and antifungal activity. In vitro cytotoxicity studies show the compounds lack any cytotoxicity. Furthermore, molecular modeling studies show plausibility of binding to Leishmania donovani topoisomerase 1 (LdTop1). Structure activity relationships reveal bulky substitutions on the pyridone nitrogen are well-tolerated, and such compounds have better binding affinity. Intramolecular hydrogen bonds confer some rigidity to the molecules, rendering a degree of planarity akin to topotecan. Taken together, we emphasis the merits of molecules possessing the 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one skeleton as potential antileishmanial agents warranting further investigation.


Assuntos
Piridonas/farmacologia , Tripanossomicidas/farmacologia , Animais , DNA Topoisomerases Tipo I/metabolismo , Estabilidade de Medicamentos , Células HEK293 , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ligação Proteica , Piridonas/síntese química , Piridonas/metabolismo , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo
16.
Cancer Chemother Pharmacol ; 89(2): 275-281, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34854953

RESUMO

PURPOSE: Irinotecan can cause high levels of diarrhea caused by toxic injury to the gastrointestinal microenvironment. Toll-like receptor 4 (TLR4) and the gut microbiome have previously been implicated in gastrointestinal toxicity and diarrhea; however, the link between these two factors has not been definitively determined. We used a tumor-bearing, intestinal epithelial cell (IEC) TLR4 knockout model (Tlr4ΔIEC) to assess microbiome changes following irinotecan treatment. We then determined if a fecal microbiota transplant (FMT) between Tlr4ΔIEC and wild-type (WT) mice altered irinotecan-induced gastrointestinal toxicity. METHODS: MC-38 colorectal cancer cells were injected into WT and Tlr4ΔIEC mice. Fecal samples were collected prior to tumor inoculation, prior to irinotecan treatment and at cull. 16S rRNA gene sequencing was used to assess changes in the microbiome. Next, FMT was used to transfer the microbiome phenotype between Tlr4ΔIEC and WT mice prior to irinotecan treatment. Gastrointestinal toxicity symptoms were assessed. RESULTS: In study 1, there were no compositional differences in the microbiome between Tlr4ΔIEC and WT mice at baseline. However, predicted functional capacity of the microbiome was different between WT and Tlr4ΔIEC at baseline and post-irinotecan. In study 2, Tlr4ΔIEC mice were protected from grade 3 diarrhea. Additionally, WT mice who did not receive FMT had more colonic damage in the colon compared to controls (P = 0.013). This was not seen in Tlr4ΔIEC mice or WT mice who received FMT (P > 0.05). CONCLUSION: Tlr4ΔIEC and WT had no baseline compositional microbiome differences, but functional differences at baseline and following irinotecan. FMT altered some aspects of irinotecan-induced gastrointestinal toxicity.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Irinotecano/farmacologia , Receptor 4 Toll-Like/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Transplante de Microbiota Fecal/métodos , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/microbiologia , Microbioma Gastrointestinal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , RNA Ribossômico 16S , Inibidores da Topoisomerase I/farmacologia
17.
Bioorg Med Chem Lett ; 57: 128517, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34952177

RESUMO

This work describes the first synthesis of diethyl 6,6a,7,11b-tetrahydro-5H-indeno[2,1-c]quinolinylphosphonates 5, diethyl 7H-indeno[2,1-c]quinolinylphosphonates 6 and diethyl 7-oxo-7H-indeno[2,1-c]quinolinylphosphonates 7, which were prepared in good to high overall yields. The synthetic route involves a multicomponent reaction of 2-phosphonateaniline, aldehydes and indene as olefin and allows the selective generation of three stereogenic centres in a short, efficient and reliable manner. The selective dehydrogenation of 1,2,3,4-tetrahydroindenoquinolines leads to the formation of corresponding indenoquinolines, and subsequent oxidation of methylene group of the indenoquinolines allows the access to indenoquinolinones.


Assuntos
Antineoplásicos/farmacologia , Indenos/farmacologia , Ácidos Fosforosos/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Indenos/síntese química , Ácidos Fosforosos/síntese química , Quinolinas/síntese química , Estereoisomerismo , Inibidores da Topoisomerase I/síntese química
18.
J Med Chem ; 65(1): 333-342, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34963283

RESUMO

Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (k2: ∼103 M-1 s-1) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of N-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by N-oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.


Assuntos
Compostos de Boro/química , Liberação Controlada de Fármacos , Irinotecano/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Inibidores da Topoisomerase I/farmacologia , Animais , Apoptose , Proliferação de Células , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Irinotecano/química , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Nanopartículas/química , Inibidores da Topoisomerase I/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Immunother Cancer ; 9(12)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34887262

RESUMO

BACKGROUND: Stimulating antitumor immunity by blocking programmed death-1 (PD-1) or its ligand (programmed death-ligand 1 (PD-L1) is a promising antitumor therapy. However, numerous patients respond poorly to PD-1/PD-L1 blockade. Unresponsiveness to immune-checkpoint blockade (ICB) can cast significant challenges to the therapeutic options for patients with hard-to-treat tumors. There is an unmet clinical need to establish new therapeutic approaches for mitigating ICB unresponsiveness in patients. In this study, we investigated the efficacy and role of low-dose antineoplastic agent SN-38 or metformin in sensitizing unresponsive tumors to respond to ICB therapy. METHODS: We assessed the significant pathological relationships between PD-L1 and FOXO3 expression and between PD-L1 and c-Myc or STAT3 expression in patients with various tumors. We determined the efficacy of low-dose SN-38 or metformin in sensitizing unresponsive tumors to respond to anti-PD-1 therapy in a syngeneic tumor system. We deciphered novel therapeutic mechanisms underlying the SN-38 and anti-PD-1 therapy-mediated engagement of natural killer (NK) or CD8+ T cells to infiltrate tumors and boost antitumor immunity. RESULTS: We showed that PD-L1 protein level was inversely associated with FOXO3 protein level in patients with ovarian, breast, and hepatocellular tumors. Low-dose SN-38 or metformin abrogated PD-L1 protein expression, promoted FOXO3 protein level, and significantly increased the animal survival rate in syngeneic mouse tumor models. SN-38 or metformin sensitized unresponsive tumors responding to anti-PD-1 therapy by engaging NK or CD8+ T cells to infiltrate the tumor microenvironment (TME) and secret interferon-γ and granzyme B to kill tumors. SN-38 suppressed the levels of c-Myc and STAT3 proteins, which controlled PD-L1 expression. FOXO3 was essential for SN38-mediated PD-L1 suppression. The expression of PD-L1 was compellingly linked to that of c-Myc or STAT3 in patients with the indicated tumors. CONCLUSION: We show that SN-38 or metformin can boost antitumor immunity in the TME by inhibiting c-Myc and STAT3 through FOXO3 activation. These results may provide novel insight into ameliorating patient response to overarching immunotherapy for tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Proteína Forkhead Box O3/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Células Matadoras Naturais/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Animais , Apoptose , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia , Irinotecano/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Microambiente Tumoral
20.
J Med Chem ; 64(24): 17979-17991, 2021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34852457

RESUMO

A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT-Se3 and CPT-Se4) were identified to show improved potency in killing cancer cells and inhibiting tumor growth in vivo. Interestingly, the intrinsic fluorescence of CPT was severely quenched by the diselenide bond. Both the selenoprodrugs were activated by glutathione with a nearly complete recovery of CPT's fluorescence. The activation of prodrugs was accompanied by the production of selenol intermediates, which catalyzed the constant conversion of glutathione and oxygen to oxidized glutathione and superoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored in the activation process prior to this study. Our work verified that integration of the diselenide unit may further enhance the parent drug's efficacy. Also, the discovery of the fluorescence quenching property of the diselenide/disulfide bond further shed light on constructing novel theranostic agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/química , Camptotecina/farmacologia , Proliferação de Células/efeitos dos fármacos , Corantes Fluorescentes/química , Pró-Fármacos/síntese química , Compostos de Selênio/química , Inibidores da Topoisomerase I/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/metabolismo , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Imagem Óptica , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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