RÉSUMÉ
Bladder cancer is a common malignancy worldwide, posing a substantial healthcare challenge. Current standard treatment regimens are primarily based on cisplatin, but their success is often limited by cisplatin resistance and associated toxicities. Therefore, there is an urgent need to develop effective and less toxic therapies as alternatives to cisplatin. We screened the activity of FDA-approved anti-cancer drugs on a panel of cisplatin-resistant bladder cancer cell lines. Based on initial responses, cabazitaxel was selected for further evaluation of its inhibitory effects on the phenotypic properties of these cells. Cabazitaxel, primarily used for metastatic castration-resistant prostate cancer, demonstrated remarkable efficacy in inhibiting colony formation, proliferation, and migration of cisplatin-resistant bladder cancer cells. This study highlights the potential of drug repurposing as a cost-effective and efficient strategy to overcome drug resistance in bladder cancer.
Sujet(s)
Antinéoplasiques , Cisplatine , Résistance aux médicaments antinéoplasiques , Taxoïdes , Tumeurs de la vessie urinaire , Humains , Tumeurs de la vessie urinaire/traitement médicamenteux , Tumeurs de la vessie urinaire/anatomopathologie , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Taxoïdes/pharmacologie , Taxoïdes/usage thérapeutique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Mouvement cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
Chemotherapy presents the main therapy of non-small cell lung cancer (NSCLC). Nevertheless, cisplatin-based therapy can be limited by drug resistance. MicroRNA (miRNA) possesses a vital regulatory function in modulating the progression as well as cisplatin resistance of NSCLC, but how miR-3195 influences NSCLC is obscure. In this work, it was discovered that miR-3195 presented definite down-regulation in NSCLC cells. Gain-of function assays revealed that overexpressing miR-3195 hindered NSCLC cell proliferation together with migration whereas induced cell apoptosis. Mechanically, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) presented the target gene of miR-3195 and was high-expressed in NSCLC cells. The repressive impacts of overexpressing miR-3195 on NSCLC cells malignant behaviors were reversed via PFKFB4 elevation. Additionally, elevated miR-3195 expression reduced cisplatin resistance of NSCLC both in vitro as well as in vivo. PFKFB4 elevation could offset the reduced cisplatin resistance caused by miR-3195 overexpression in NSCLC cells. In conclusion, this work clarified miR-3195 repressed NSCLC cell proliferation, migration, as well as cisplatin resistance by modulating PFKFB4. Our study might provide a promising clue to promote the anti-tumor effects of chemotherapy.
Sujet(s)
Apoptose , Carcinome pulmonaire non à petites cellules , Mouvement cellulaire , Prolifération cellulaire , Cisplatine , Résistance aux médicaments antinéoplasiques , Régulation de l'expression des gènes tumoraux , Tumeurs du poumon , microARN , Phosphofructokinase-2 , Animaux , Humains , Souris , Apoptose/effets des médicaments et des substances chimiques , Apoptose/génétique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Mouvement cellulaire/génétique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/génétique , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Souris de lignée BALB C , Souris nude , microARN/génétique , microARN/métabolisme , Phosphofructokinase-2/génétique , Phosphofructokinase-2/métabolismeRÉSUMÉ
BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
Sujet(s)
Tumeurs des canaux biliaires , Cholangiocarcinome , Lysyloxidase , Cholangiocarcinome/traitement médicamenteux , Cholangiocarcinome/anatomopathologie , Animaux , Tumeurs des canaux biliaires/traitement médicamenteux , Tumeurs des canaux biliaires/anatomopathologie , Lysyloxidase/antagonistes et inhibiteurs , Souris , Humains , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologie , Mâle , Amino-acid oxidoreductases/antagonistes et inhibiteurs , Modèles animaux de maladie humaine , Lignée cellulaire tumoraleRÉSUMÉ
The efficiency of combinations of cytostatics cisplatin and adriamycin with antioxidant sodium 3-(3'-tert-butyl-4-hydroxyphenyl)propyl thiosulfate (TS-13), and nitric oxide (NO) donor NaNO2 was evaluated on two drug-resistant strains of leukemia P388 with changed redox-status of cells. Simultaneous use of both NO donor and TS-13 in combinations with the cytostatics did not increase the efficiency of therapy. In addition, antioxidant activity of TS-13, NaNO2, and their combinations was studied by the method of luminol-dependent chemiluminescence on the model systems with the use of the homogenized cells of sensitive strain and two drug-resistant strains of leukemia P388. It was shown that TS-13 and NO donor produced opposite effects: TS-13 decreased, while NO donor increased the content of free radicals in the model system. Combinations of antioxidant TS-13 and NO donor should be used with consideration for the redox-status of tumor treated.
Sujet(s)
Antioxydants , Cisplatine , Doxorubicine , Résistance aux médicaments antinéoplasiques , Leucémie P388 , Donneur d'oxyde nitrique , Oxydoréduction , Animaux , Souris , Oxydoréduction/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Doxorubicine/pharmacologie , Leucémie P388/traitement médicamenteux , Leucémie P388/anatomopathologie , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Donneur d'oxyde nitrique/pharmacologie , Thiosulfates/pharmacologie , Nitrite de sodium/pharmacologie , Lignée cellulaire tumorale , Antinéoplasiques/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologieRÉSUMÉ
Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.
Sujet(s)
Antinéoplasiques , Plasticité cellulaire , Résistance aux médicaments antinéoplasiques , Tumeurs , Humains , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Tumeurs/anatomopathologie , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Plasticité cellulaire/effets des médicaments et des substances chimiques , Plasticité cellulaire/génétiqueRÉSUMÉ
UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.
Sujet(s)
Tumeurs du sein , Résistance aux médicaments antinéoplasiques , Récepteur alpha des oestrogènes , Rétrocontrôle physiologique , Ubiquitin-conjugating enzymes , Humains , Ubiquitin-conjugating enzymes/métabolisme , Ubiquitin-conjugating enzymes/génétique , Tumeurs du sein/métabolisme , Tumeurs du sein/anatomopathologie , Tumeurs du sein/génétique , Tumeurs du sein/traitement médicamenteux , Femelle , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Récepteur alpha des oestrogènes/métabolisme , Animaux , Évolution de la maladie , Souris nude , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris , Apoptose/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Fulvestrant/pharmacologie , Ubiquitination , Cellules MCF-7Sujet(s)
DNA modification methylases , Enzymes de réparation de l'ADN , Résistance aux médicaments antinéoplasiques , Glioblastome , Cellules souches tumorales , Témozolomide , Régulation positive , Glioblastome/traitement médicamenteux , Glioblastome/génétique , Glioblastome/métabolisme , Glioblastome/anatomopathologie , Témozolomide/usage thérapeutique , Témozolomide/pharmacologie , Humains , Cellules souches tumorales/effets des médicaments et des substances chimiques , Cellules souches tumorales/métabolisme , DNA modification methylases/métabolisme , DNA modification methylases/génétique , Enzymes de réparation de l'ADN/génétique , Enzymes de réparation de l'ADN/métabolisme , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Régulation positive/effets des médicaments et des substances chimiques , Protéines suppresseurs de tumeurs/génétique , Protéines suppresseurs de tumeurs/métabolisme , Antinéoplasiques alcoylants/usage thérapeutique , Antinéoplasiques alcoylants/pharmacologieRÉSUMÉ
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
Sujet(s)
Résistance aux médicaments antinéoplasiques , Tumeurs de la tête et du cou , Cellules souches mésenchymateuses , Humains , Tumeurs de la tête et du cou/anatomopathologie , Tumeurs de la tête et du cou/traitement médicamenteux , Tumeurs de la tête et du cou/thérapie , Tumeurs de la tête et du cou/immunologie , Cellules souches mésenchymateuses/métabolisme , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Carcinogenèse/anatomopathologie , Carcinogenèse/effets des médicaments et des substances chimiques , Animaux , Transplantation de cellules souches mésenchymateusesRÉSUMÉ
Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter's tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.
Sujet(s)
Glioblastome , , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X , Glioblastome/métabolisme , Glioblastome/traitement médicamenteux , Glioblastome/anatomopathologie , Humains , Animaux , Lignée cellulaire tumorale , Souris , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X/métabolisme , Protéine-1 de complémentation croisée de la réparation des lésions induites par les rayons X/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Souris nude , Cellules souches tumorales/métabolisme , Cellules souches tumorales/effets des médicaments et des substances chimiques , Cellules souches tumorales/anatomopathologie , Protéines membranaires/métabolisme , Protéines de transport/métabolisme , Hormones thyroïdiennes/métabolisme , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/traitement médicamenteux , Tumeurs du cerveau/anatomopathologie , Aldehyde oxidoreductases , Oxidoreductases acting on CH-NH group donorsSujet(s)
Résistance aux médicaments antinéoplasiques , Humains , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Nicotinamide/analogues et dérivés , PyrazolesRÉSUMÉ
Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Résistance aux médicaments antinéoplasiques , Épigenèse génétique , Récepteurs ErbB , Glycolyse , Tumeurs du poumon , Inhibiteurs de protéines kinases , Transaminases , Humains , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Transaminases/génétique , Transaminases/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Glycolyse/effets des médicaments et des substances chimiques , Glycolyse/génétique , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Épigenèse génétique/effets des médicaments et des substances chimiques , Épigenèse génétique/génétique , Souris , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Acrylamides/pharmacologie , Animaux , Dérivés de l'aniline/pharmacologie , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Protéines tumorales/génétique , Protéines tumorales/métabolisme , Indoles , PyrimidinesRÉSUMÉ
A novel series of substituted thiazolo[5,4-b]pyridine analogues were rationally designed and synthesized via a multi-step synthetic pathway, including Suzuki cross-coupling reaction. The anticancer activity of all forty-five synthesized derivatives was evaluated against HCC827, H1975, and A549 cancer cell lines utilizing the standard MTT assay. A significant number of the thiazolo[5,4-b]pyridine derivatives exhibited potent anticancer activity. Notably, compounds 10b, 10c, 10h, 10i, and 10k emerged as the most promising anticancer agents. The lead compound, N-(3-(6-(2-aminopyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-methylphenyl)-2,5-difluorobenzenesulfonamide (10k), displayed remarkable potency with IC50 values of 0.010 µM, 0.08 µM, and 0.82 µM against the HCC827, NCI-H1975 and A-549 cancer cell lines, respectively, which were comparable to the clinically approved drug Osimertinib. Importantly, the potent derivatives 10b, 10c, 10h, 10i, and 10k exhibited selective cytotoxicity towards cancer cells and showing no toxicity against the normal BEAS-2B cell line at concentrations exceeding 35 µM. Mechanistic studies revealed that the active compound 10k acts as an EGFR-TK autophosphorylation inhibitor in HCC827 cells. Furthermore, apoptosis assays demonstrated that compound 10k induced substantial early apoptosis (31.9 %) and late apoptosis (8.8 %) in cancer cells, in contrast to the control condition exhibiting only 2.0 % early and 1.6 % late apoptosis. Molecular docking simulations of the synthesized compounds revealed that they formed essential hinge interactions and established hydrogen bonding with Cys797, indicating potential target engagement. These findings highlight the potential of the synthesized thiazolo [(Woodburn, 1999; Zigrossi et al., 2022) 5,45,4-b]pyridine derivatives as promising anticancer agents, warranting further investigation for the development of novel targeted therapies against non-small cell lung cancer.
Sujet(s)
Antinéoplasiques , Carcinome pulmonaire non à petites cellules , Prolifération cellulaire , Conception de médicament , Tests de criblage d'agents antitumoraux , Récepteurs ErbB , Tumeurs du poumon , Mutation , Inhibiteurs de protéines kinases , Pyridines , Humains , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Relation structure-activité , Pyridines/pharmacologie , Pyridines/composition chimique , Pyridines/synthèse chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Structure moléculaire , Thiazoles/pharmacologie , Thiazoles/composition chimique , Thiazoles/synthèse chimique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Simulation de docking moléculaireRÉSUMÉ
Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. PCa that relapses after hormonal therapies, referred to as castration resistant PCa (CRPC), often presents with metastases (mCRPC) that are the major cause of mortality. The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. Mechanistically, resistance arises through upregulation of multidrug resistance (MDR) proteins such as MDR1/ABCB1, making ABCB1 an attractive therapeutic target. Yet, ABCB1 inhibitors failed to be clinically useful due to low specificity and toxicity issues. To study taxanes resistance, we produced CBZ resistant C4-2B cells (RC4-2B) and documented resistance to both CBZ and DTX in cell culture and in 3D prostaspheres settings. RNAseq identified increased expression of ABCB1 in RC4-2B, that was confirmed by immunoblotting and immunofluorescent analysis. ABCB1-specific inhibitor elacridar reversed CBZ and DTX resistance in RC4-2B cells, confirming ABCB1-mediated resistance mechanism. In a cell-based screen using a curated library of cytotoxic drugs, we found that DNA damaging compounds Camptothecin (CPT) and Cytarabine (Ara-C) overcame resistance as seen by similar cytotoxicity in parental C4-2B and resistant RC4-2B. Further, these compounds were cytotoxic to multiple PC cells resistant to taxanes with high ABCB1 expression and, therefore, can be used to conquer the acquired resistance to taxanes in PCa. Finally, inhibition of cyclin-dependent kinases 4/6 (CDK4/6) with small molecule inhibitors (CDK4/6i) potentiated cytotoxic effect of CPT or Ara-C in both parental and resistant cells. Overall, our findings indicate that DNA damaging agents CPT and Ara-C alone or in combination with CDK4/6i can be suggested as a new treatment regimen in CRPC patients, including those that are resistant to taxanes.
Sujet(s)
Sous-famille B de transporteurs à cassette liant l'ATP , Docetaxel , Multirésistance aux médicaments , Résistance aux médicaments antinéoplasiques , Tumeurs prostatiques résistantes à la castration , Taxoïdes , Humains , Mâle , Tumeurs prostatiques résistantes à la castration/traitement médicamenteux , Tumeurs prostatiques résistantes à la castration/anatomopathologie , Tumeurs prostatiques résistantes à la castration/métabolisme , Tumeurs prostatiques résistantes à la castration/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Sous-famille B de transporteurs à cassette liant l'ATP/métabolisme , Sous-famille B de transporteurs à cassette liant l'ATP/génétique , Lignée cellulaire tumorale , Docetaxel/pharmacologie , Multirésistance aux médicaments/effets des médicaments et des substances chimiques , Taxoïdes/pharmacologie , Taxoïdes/usage thérapeutique , Antinéoplasiques/pharmacologieRÉSUMÉ
Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure and cancer recurrence in non-small cell lung cancer (NSCLC). Approximately 30% of patients with EGFR-activating mutations exhibit primary resistance to EGFR-TKIs. However, the potential mechanisms of primary resistance to EGFR-TKIs remain poorly understood. Recent studies have shown that increased expression of programmed death ligand-1 (PD-L1) is associated with EGFR-TKIs resistance. Therefore, the present study aimed to investigate the mechanism of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma (LUAD) cells. We found that PD-L1 was associated with poor prognosis in patients with EGFR-mutant LUAD, while the combination of EGFR-TKIs with chemotherapy could improve its therapeutic efficacy. In vitro and in vivo experiments revealed that PD-L1 promoted the proliferation and autophagy and inhibited the apoptosis of LUAD cells. Mechanistic studies demonstrated that upregulation of PD-L1 was critical in inducing autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, which was beneficial for tumor progression and the development of gefitinib resistance. Furthermore, we found that gefitinib combined with pemetrexed could synergistically enhance antitumor efficacy in PD-L1-overexpression LUAD cells. Overall, our study demonstrated that PD-L1 contributed to primary resistance to EGFR-TKIs in EGFR-mutant LUAD cells, which may be mediated by inducing autophagy via the MAPK signaling pathway. These findings not only help improve the prognosis of patients with EGFR-mutant LUAD but also provide a reference for the research of other cancer types.
Sujet(s)
Adénocarcinome pulmonaire , Autophagie , Antigène CD274 , Résistance aux médicaments antinéoplasiques , Récepteurs ErbB , Tumeurs du poumon , Système de signalisation des MAP kinases , Mutation , Inhibiteurs de protéines kinases , Humains , Autophagie/effets des médicaments et des substances chimiques , Autophagie/génétique , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Antigène CD274/métabolisme , Antigène CD274/génétique , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/anatomopathologie , Adénocarcinome pulmonaire/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Animaux , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Mutation/génétique , Souris , Souris nude , Femelle , Mâle , Géfitinib/pharmacologie , Géfitinib/usage thérapeutique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiques , Souris de lignée BALB CRÉSUMÉ
Despite advances in therapies, glioblastoma (GBM) recurrence is almost inevitable due to the aggressive growth behavior of GBM cells and drug resistance. Temozolomide (TMZ) is the preferred drug for GBM chemotherapy, however, development of TMZ resistance is over 50% cases in GBM patients. To investigate the mechanism of TMZ resistance and invasive characteristics of GBM, analysis of combined RNA-seq and ChIP-seq was performed in GBM cells in response to TMZ treatment. We found that the PERK/eIF2α/ATF4 signaling was significantly upregulated in the GBM cells with TMZ treatment, while blockage of ATF4 effectively inhibited cell migration and invasion. SPHK1 expression was transcriptionally upregulated by ATF4 in GBM cells in response to TMZ treatment. Blockage of ATF4-SPHK1 signaling attenuated the cellular and molecular events in terms of invasive characteristics and TMZ resistance. In conclusion, GBM cells acquired chemoresistance in response to TMZ treatment via constant ER stress. ATF4 transcriptionally upregulated SPHK1 expression to promote GBM cell aggression and TMZ resistance. The ATF4-SPHK1 signaling in the regulation of the transcription factors of EMT-related genes could be the underlying mechanism contributing to the invasion ability of GBM cells and TMZ resistance. ATF4-SPHK1-targeted therapy could be a potential strategy against TMZ resistance in GBM patients.
Sujet(s)
Mouvement cellulaire , Résistance aux médicaments antinéoplasiques , Stress du réticulum endoplasmique , Glioblastome , Invasion tumorale , Transduction du signal , Témozolomide , Animaux , Humains , Facteur de transcription ATF-4/métabolisme , Facteur de transcription ATF-4/génétique , Tumeurs du cerveau/anatomopathologie , Tumeurs du cerveau/génétique , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/traitement médicamenteux , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Glioblastome/anatomopathologie , Glioblastome/génétique , Glioblastome/métabolisme , Glioblastome/traitement médicamenteux , Souris nude , Phosphotransferases (Alcohol Group Acceptor)/métabolisme , Phosphotransferases (Alcohol Group Acceptor)/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Témozolomide/pharmacologie , Témozolomide/usage thérapeutiqueRÉSUMÉ
AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy. METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models. RESULTS: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance. CONCLUSIONS: Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.
Sujet(s)
Tumeurs du sein , Résistance aux médicaments antinéoplasiques , Nanoparticules , Récepteur ErbB-2 , Trastuzumab , Tests d'activité antitumorale sur modèle de xénogreffe , Trastuzumab/pharmacologie , Humains , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Animaux , Souris , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Récepteur ErbB-2/métabolisme , Récepteur ErbB-2/antagonistes et inhibiteurs , Lignée cellulaire tumorale , Nanoparticules/composition chimique , Souris transgéniques , Antinéoplasiques immunologiques/pharmacologie , Receptor-Like Protein Tyrosine Phosphatases, Class 3/métabolisme , Receptor-Like Protein Tyrosine Phosphatases, Class 3/antagonistes et inhibiteurs , Receptor-Like Protein Tyrosine Phosphatases, Class 3/génétique , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks an actionable target with limited treatment options beyond conventional chemotherapy. Therapeutic failure is often encountered due to inherent or acquired resistance to chemotherapy. Previous studies implicated PI3K/Akt/mTOR signaling pathway in cancer stem cells (CSCs) enrichment and hence chemoresistance. The present study aimed at investigating the potential effect of piperine (PIP), an amide alkaloid isolated from Piper nigrum, on enhancing the sensitivity of TNBC cells to doxorubicin (DOX) in vitro on MDA-MB-231 cell line and in vivo in an animal model of Ehrlich ascites carcinoma solid tumor. Results showed a synergistic interaction between DOX and PIP on MDA-MB-231 cells. In addition, the combination elicited enhanced suppression of PI3K/Akt/mTOR signaling that paralleled an upregulation in this pathway's negative regulator, PTEN, along with a curtailment in the levels of the CSCs surrogate marker, aldehyde dehydrogenase-1 (ALDH-1). Meanwhile, in vivo investigations demonstrated the potential of the combination regimen to enhance necrosis while downregulating PTEN and curbing PI3K levels as well as p-Akt, mTOR, and ALDH-1 immunoreactivities. Notably, the combination failed to change cleaved poly-ADP ribose polymerase levels suggesting a pro-necrotic rather than pro-apoptotic mechanism. Overall, these findings suggest a potential role of PIP in decreasing the resistance to DOX in vitro and in vivo, likely by interfering with the PI3K/Akt/mTOR pathway and CSCs.
Sujet(s)
Alcaloïdes , Benzodioxoles , Doxorubicine , Cellules souches tumorales , Phosphatidylinositol 3-kinases , Pipéridines , Amides gras polyinsaturés N-alkylés , Protéines proto-oncogènes c-akt , Transduction du signal , Sérine-thréonine kinases TOR , Tumeurs du sein triple-négatives , Doxorubicine/pharmacologie , Amides gras polyinsaturés N-alkylés/pharmacologie , Pipéridines/pharmacologie , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/anatomopathologie , Cellules souches tumorales/effets des médicaments et des substances chimiques , Cellules souches tumorales/métabolisme , Humains , Alcaloïdes/pharmacologie , Benzodioxoles/pharmacologie , Animaux , Protéines proto-oncogènes c-akt/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Femelle , Lignée cellulaire tumorale , Sérine-thréonine kinases TOR/métabolisme , Synergie des médicaments , Souris , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction. METHODS: A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the efficacy of chiauranib combined with chemotherapy. Chinese patients with recurrent ovarian cancer were enrolled. Eligible patients received chiauranib combined with a maximum of six cycles of chemotherapy: etoposide (CE group) or weekly-paclitaxel (CP group). Patients, who exhibited a complete or partial response, or stable disease following combo treatment, progressed to maintenance phase to receive chiauranib monotherapy. Primary endpoint was progression-free survival (PFS) according to RECIST v1.1. RESULTS: From November 2017 to March 2019, 25 patients were enrolled in a phase 1b study and a median PFS of 3.7 months (95% CI 1.8-NE) was achieved by chiauranib monotherapy. From July 2019 to December 2020, a total of 47 patients were enrolled in the phase II study. One CP patient did not receive the study drugs, and three patients withdrew before the first tumor assessment. Thus, 43 patients (CE group: 22 patients; CP group: 21 patients) were included in the evaluation. The median PFS was 5·4 months (95% CI 2·8-5·6) and 5·6 months (95% CI 3·4-7·0), respectively. CONCLUSIONS: This was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with ovarian cancer. The administration of chiauranib along with etoposide or weekly-paclitaxel significantly enhanced the efficacy with manageable adverse events. This warrants further clinical studies on this novel treatment. A phase III study is promising and ongoing. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT03901118 (phase II) and NCT03166891 (phase Ib).
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Résistance aux médicaments antinéoplasiques , Tumeurs de l'ovaire , Humains , Femelle , Adulte d'âge moyen , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/anatomopathologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Sujet âgé , Adulte , Résultat thérapeutique , Paclitaxel/usage thérapeutique , Paclitaxel/administration et posologie , Paclitaxel/effets indésirablesRÉSUMÉ
Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.
Sujet(s)
Tumeurs du sein , Prolifération cellulaire , Cytostatiques , Doxorubicine , Résistance aux médicaments antinéoplasiques , Metformine , Humains , Metformine/pharmacologie , Cellules MCF-7 , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/métabolisme , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Doxorubicine/pharmacologie , Femelle , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cytostatiques/pharmacologie , Survie cellulaire/effets des médicaments et des substances chimiques , Multirésistance aux médicaments/effets des médicaments et des substances chimiques , Hypoglycémiants/pharmacologieRÉSUMÉ
Chlorambucil-platinum(IV) prodrugs exhibit multi-mechanistic chemotherapeutic activity with promising anticancer potential. The platinum(II) precursors of the prodrugs have been previously found to induce changes in the microtubule cytoskeleton, specifically actin and tubulin of HT29 colon cells, while chlorambucil alkylates the DNA. These prodrugs demonstrate significant anticancer activity in 2D cell and 3D spheroid viability assays. A notable production of reactive oxygen species has been observed in HT29 cells 72 h post treatment with prodrugs of this type, while the mitochondrial membrane potential was substantially reduced. The cellular uptake of the chlorambucil-platinum(IV) prodrugs, assessed by ICP-MS, confirmed that active transport was the primary uptake mechanism, with platinum localisation identified primarily in the cytoskeletal fraction. Apoptosis and necrosis were observed at 72 h of treatment as demonstrated by Annexin V-FITC/PI assay using flow cytometry. Immunofluorescence measured via confocal microscopy showed significant changes in actin and tubulin intensity and in architecture. Western blot analysis of intrinsic and extrinsic pathway apoptotic markers, microtubule cytoskeleton markers, cell proliferation markers, as well as autophagy markers were studied post 72 h of treatment. The proteomic profile was also studied with a total of 1859 HT29 proteins quantified by mass spectroscopy, with several dysregulated proteins. Network analysis revealed dysregulation in transcription, MAPK markers, microtubule-associated proteins and mitochondrial transport dysfunction. This study confirms that chlorambucil-platinum(IV) prodrugs are candidates with promising anticancer potential that act as multi-mechanistic chemotherapeutics.