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1.
Med Oncol ; 39(12): 194, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071289

RESUMO

The present study aimed to assess the influence of ciprofloxacin (CIP) against the doxorubicin (DOX)-resistant androgen-independent prostate cancer DU145 cells. The DOX-resistant DU145 (DU145/DOX20) cells were established by exposing DU145 cells to the increasing concentrations of DOX. The antiproliferative effect of CIP was examined through employing MTT, colony formation, and 3D culture assays. DU145/DOX20 cells exhibited a twofold higher IC50 value for DOX, an increased ABCB1 transporter activity, and some morphological changes accompanied by a decrease in spheroid size, adhesive and migration potential compared to DU145 cells. CIP (5 and 25 µg mL-1) resulted in a higher reduction in the viability of DU145/DOX20 cells than in DU145 cells. DU145/DOX20 cells were more resistant to CIP in 3D culture compared to the 2D one. No spheroid formation was observed for DU145/DOX20 cells treated with DOX and CIP combination. CIP and DOX, alone or in combination, significantly reduced the growth of DU145 spheroids. CIP in combination with 20 nM DOX prevented the colony formation of DU145 cells. The clonogenicity of DU145/DOX20 cells could not be estimated due to their low adhesive potential. CIP alone caused a significant reduction in the migration of DU145 cells and resulted in a more severe decrease in the wound closure ability of DOX-exposed ones. We identified that CIP enhanced DOX sensitivity in DU145 and DU145/DOX20 cells. This study suggested the co-delivery of low concentrations of CIP and DOX may be a promising strategy in treating the DOX-resistant and -sensitive hormone-refractory prostate cancer.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias da Próstata , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Masculino , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
2.
J Exp Clin Cancer Res ; 41(1): 267, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071480

RESUMO

BACKGROUND: Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments. METHODS: A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC. RESULTS: The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3'-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance. CONCLUSIONS: Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Trifosfato de Adenosina , Carcinogênese/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/genética , Doxorrubicina/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
3.
Biomed Pharmacother ; 153: 113443, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076558

RESUMO

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.


Assuntos
Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Neoplasias Pulmonares , Animais , Apoptose , Autofagia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Receptores ErbB , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Fosfatidilinositol 3-Quinases , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR/metabolismo
4.
Biomed Pharmacother ; 153: 113484, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076583

RESUMO

Increasing mitochondrial fusion by intra-tumoral grafting of membrane-fused mitochondria created with Pep-1 conjugation (P-Mito) contributes to breast cancer treatment, but it needs to be validated. Using mitochondrial division inhibitor-1 (Mdivi-1, Mdi) to disturb mitochondrial dynamics, we showed that the antitumor action of P-Mito in a mouse model of triple-negative breast cancer depends upon mitochondrial fusion and that Mdi treatment alone is ineffective. P-Mito significantly enhanced Doxorubicin (Dox) sensitivity by inducing mitochondrial fusion and mitophagy, and the same efficiency was also achieved with Mdi by inhibiting mitophagy. Cell death was induced via the p53 pathway and AIF nuclear translocation in the case of P-Mito, versus the caspase-dependent pathway for Mdi. Notably, both mitochondrial treatments reduced oxidative stress and blood vessel density of xenograft tumors, especially P-Mito, which was accompanied by inhibition of nuclear factor kappa-B activation. Furthermore, through enrichment analysis, four microRNAs in serum microvesicles induced by P-Mito caused expression of predicted targets via the PI3K-Akt pathway, and significantly impacted regulation of nuclear processes and myeloid cell differentiation. Clustering of gene-sets implicated a major steroid catabolic network. This study showed diverse roles of mitochondria in breast cancer and revealed effective adjuvant therapy targeting mitochondrial fusion and mitophagy.


Assuntos
Mitofagia , Neoplasias de Mama Triplo Negativas , Animais , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Humanos , Camundongos , Mitocôndrias , Dinâmica Mitocondrial , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
5.
J Enzyme Inhib Med Chem ; 37(1): 2566-2573, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36120947

RESUMO

Tumour-associated macrophages (TAMs) support tumour development and have emerged as important regulators of therapeutic response to cytostatic agents. To target TAMs, we have developed a novel drug delivery approach which induces drug release as it inhibits cysteine cathepsin activity. This inhibitory prodrug (IPD) approach establishes a self-regulated system where drug release stops after all cysteine cathepsins are inhibited. This could improve the therapeutic window for drugs with severe side effects. We demonstrate and characterise this self-regulation concept with a fluorogenic IPD model. Next, we applied this IPD strategy to deliver cytotoxic drugs, as doxorubicin and monomethyl auristatin E, which are efficiently released and dose-dependently eliminate RAW264.7 macrophages. Lastly, by exploiting the increased cathepsin activity in TAM-like M2-polarised primary macrophages, we show that IPD-Dox selectively eliminates M2 over M1 macrophages. This demonstrates the potential of our IPD strategy for selective drug delivery and modulation of the tumour microenvironment.


Assuntos
Citostáticos , Pró-Fármacos , Catepsinas , Cisteína , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Pró-Fármacos/farmacologia
6.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077042

RESUMO

Carbon nanomaterials have received increasing attention in drug-delivery applications because of their distinct properties and structures, including large surface areas, high conductivity, low solubility in aqueous media, unique chemical functionalities, and stability at the nano-scale size. Particularly, they have been used as nano-carriers and mediators for anticancer drugs such as Cisplatin, Camptothecin, and Doxorubicin. Cancer has become the most challenging disease because it requires sophisticated therapy, and it is classified as one of the top killers according to the World Health Organization records. The aim of the current work is to study and investigate the mechanism of combination between single-walled carbon nanotubes (SWCNTs) and fullerene derivatives (CN-[OH]ß) as mediators, and anticancer agents for photodynamic therapy directly to destroy the infected cells without damaging the normal ones. Here, we obtain a bio-medical model to determine the efficiency of the usefulness of Doxorubicin (DOX) as an antitumor agent conjugated with SWCNTs with variant radii r and fullerene derivative (CN-[OH]ß). The two sub-models are obtained mathematically to evaluate the potential energy arising from the DOX-SWCNT and DOX-(CN-[OH]ß) interactions. DOX modelled as two-connected spheres, small and large, each interacting with different SWCNTs (variant radii r) and fullerene derivatives CN-[OH]ß, formed based on the number of carbon atoms (N) and the number of hydroxide molecules (OH) (ß), respectively. Based on our obtained results, we find that the most favorable carbon nanomaterial is the SWCNT (r = 15.27 Å), followed by fullerene derivatives CN-(OH)22, CN-(OH)20, and CN-(OH)24, with minimum energies of -38.27, -33.72, -32.95, and -29.11 kcal/mol.


Assuntos
Antineoplásicos , Fulerenos , Nanotubos de Carbono , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Fulerenos/uso terapêutico , Hidróxidos , Nanotubos de Carbono/química , Neoplasias/tratamento farmacológico , Preparações Farmacêuticas
7.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077085

RESUMO

The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett-Brown substituent were correlated.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Hidroxiquinolinas , Antineoplásicos/farmacologia , Compostos de Benzilideno , Citotoxinas , Doxorrubicina/farmacologia , Humanos
8.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077102

RESUMO

To endow the polymeric prodrug with smart properties through a safe and simple method, matrix metalloproteinase (MMPs) responsive peptide GPLGVRGDG was introduced into the block copolymer to prepare TPGS3350-GPLGVRGDG-DOX&DOX micelles, where TPGS3350 is D-α-tocopheryl polyethylene glycol 3350 succinate. During the doxorubicin delivery, the cleavage of the peptide chain triggers de-PEGylation, and the remaining VRGDG sequence was retained on the surface of the micelles, which can act as a ligand to facilitate cell uptake. Moreover, the cytotoxicity of TPGS3350-GPLGVRGDG-DOX&DOX micelles against 4T1 cells was significantly improved, compared with TPGS3350-GPLGVRG-DOX&DOX micelles and TPGS3350-DOX&DOX micelles. During in vivo studies, TPGS3350-GPLGVRGDG-DOX&DOX micelles exhibited good anticancer efficacy with long circulation in the body and more efficient accumulation at the tumor site. Therefore, TPGS3350-GPLGVRGDG-DOX&DOX micelles have improved antitumor activity and reduced toxic side effects. This work opens new potential for exploring the strategy of drug delivery in clinical applications.


Assuntos
Micelas , Polietilenoglicóis , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/química , Polietilenoglicóis/química , Polímeros
9.
AAPS PharmSciTech ; 23(7): 255, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109444

RESUMO

Doxorubicin (DOX) is a chemotherapeutic agent that has been used in the treatment of breast cancer. However, serious toxic effects have limited its use, mainly cardiotoxicity. To minimize the adverse effects, liposomal preparations containing DOX have been developed. These preparations can reach the target in the tumor region as well as bypass the resistance-related problems. An alternative to increased therapeutic efficacy may be the fusion of liposomes with exosomes released from tumor cells to facilitate membrane and fusion interactions, achieving greater cell uptake. Thus, the purpose of this study was the fusion of exosomes derived from breast tumor cells with long-circulating and pH-sensitive liposomes loading DOX (ExoSpHL-DOX) for the treatment of breast cancer. The mean diameter of ExoSpHL-DOX was 100.8 ± 7.8 nm, the polydispersity index was 0.122 ± 0.004, and the encapsulated DOX content was equal to 83.5 ± 2.5%. The fusion of exosomes with long-circulating and pH-sensitive liposomes was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy, and nano-flow cytometry. The physicochemical characteristics of ExoSpHL-DOX were maintained for 60 days, at 4 °C. The study of the release of DOX from ExoSpHL-DOX in dilution media with different pH values showed the pH sensitivity characteristic of the nanosystem, since 96.6 ± 0.2% of DOX was released from ExoSpHL-DOX at pH 5.0, while at pH 7.4, the release was 70.1 ± 1.7% in the medium. The cytotoxic study against the breast cancer cell line demonstrated that ExoSpHL-DOX treatment significantly reduced the cancer cell viability.


Assuntos
Antineoplásicos , Neoplasias da Mama , Exossomos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Exossomos/patologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química
10.
Nat Commun ; 13(1): 5424, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109556

RESUMO

Nanocapsules that collapse in response to guanosine triphosphate (GTP) have the potential as drug carriers for efficiently curing diseases caused by cancer and RNA viruses because GTP is present at high levels in such diseased cells and tissues. However, known GTP-responsive carriers also respond to adenosine triphosphate (ATP), which is abundant in normal cells as well. Here, we report the elaborate reconstitution of microtubule into a nanocapsule that selectively responds to GTP. When the tubulin monomer from microtubule is incubated at 37 °C with a mixture of GTP (17 mol%) and nonhydrolysable GTP* (83 mol%), a tubulin nanosheet forms. Upon addition of photoreactive molecular glue to the resulting dispersion, the nanosheet is transformed into a nanocapsule. Cell death results when a doxorubicin-containing nanocapsule, after photochemically crosslinked for properly stabilizing its shell, is taken up into cancer cells that overexpress GTP.


Assuntos
Nanocápsulas , Tubulina (Proteína) , Trifosfato de Adenosina/metabolismo , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Guanosina Trifosfato/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo
11.
Physiol Rep ; 10(17): e15448, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36065849

RESUMO

Chronic kidney disease (CKD) is a priority health problem affecting 36% of Egyptians. Adipose-derived mesenchymal stem cells (ADMSCs) have multidifferentiation capacity and the ability to restore several types of cells including damaged renal cells. Granulocyte colony-stimulating factor (G-CSF) is known to mobilize hematopoietic stem cells from bone marrow to the peripheral circulation. The aim of this study was to compare the effect of endogenous CD34+ cells mobilization and exogenous ADMSCs administration in the treatment of a rat model of adriamycin (ADR)-induced CKD. A total of 48 male albino rats of the local strain (200 ± 50 g) were equally divided into four groups: control negative, ADR (control positive), ADMSCs group, and G-CSF group. Six rats from each group were sacrificed after 4 weeks and the other 6 after 12 weeks. Renal function was assessed frequently by measuring serum creatinine, albumin, urea, 24-h urinary protein level, and hemoglobin level throughout the study. Oxidative stress markers malondialdehyde (MDA) and total antioxidant (TAO) were measured on day 28. CD-34+ cell percentage was measured on day 9. After the sacrification of the rats, kidneys were removed for histopathological assessment. Results revealed that both ADMSCs and G-CSF significantly improved serum creatinine, albumin, urea, 24-h urinary protein level, and histopathological damage score, with the G-CSF-treated group showing better improvement in 24-h urinary protein level, serum albumin, and histopathological damage score compared with ADMSCs-treated group. The G-CSF group also had significantly higher levels of CD34+ cells. Oxidative stress markers (MDA and TAO) levels were significantly improved with both therapies. We conclude that mobilization of endogenous hematopoietic stem cells by G-CSF is more effective than exogenously injected ADMSCs in protecting the kidneys against AD-induced toxicity.


Assuntos
Fator Estimulador de Colônias de Granulócitos , Insuficiência Renal Crônica , Albuminas , Células da Medula Óssea , Creatinina , Doxorrubicina/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Insuficiência Renal Crônica/terapia , Ureia
12.
Commun Biol ; 5(1): 955, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36097051

RESUMO

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.


Assuntos
Receptores de Estrogênio , Remodelação Ventricular , Animais , Doxorrubicina/farmacologia , Camundongos , Miócitos Cardíacos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo
13.
Int J Mol Sci ; 23(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36077544

RESUMO

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.


Assuntos
Cardiotoxicidade , Fator 2 Relacionado a NF-E2 , Animais , Apoptose , Compostos Benzidrílicos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , Fibrose , Glucosídeos , Hipertrofia/metabolismo , Inflamação/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Remodelação Ventricular
14.
Cells ; 11(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36078050

RESUMO

Hepatocellular carcinoma (HCC) is one of the dominating causes of cancer-related death throughout the world. Treatment options for patients with HCC vary, however, the lack of effective targeted drugs is the major reason for death in advanced HCC patients. In this study, a delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed. In this system, we initially erased terminal linked α2-3 and α2-6 sialic acids on the surface of EVs by neuraminidase. The exhibition of galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in treated MSC-EVs can specifically be recognized by asialoglycoprotein receptor (ASGPR) of hepatoma cells. Compared to free Dox and Dox-loaded EVs, desialylated EVs loaded with Dox significantly presented the improved cellular uptake, prioritized targeting efficacy, and had a better inhibiting effect in vitro and in vivo. Overall, the results of the present study of the demonstrated delivery system using desialylated MSC-EVs suggest its therapeutic potential for HCC.


Assuntos
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Células-Tronco Mesenquimais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Vesículas Extracelulares/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Células-Tronco Mesenquimais/metabolismo
15.
Nutrients ; 14(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36079891

RESUMO

Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer.


Assuntos
Senescência Celular , Neoplasias , Doxorrubicina/farmacologia , Humanos , Neoplasias/metabolismo
16.
Bioorg Chem ; 128: 106043, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36058118

RESUMO

Novel tetracyclic pyrazolo[1,5-a]pyrimidine derivatives; namely benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2-amines 6a-e and benzo[3,4]cyclohepta[1,2-e]pyrazolo[1,5-a]pyrimidin-2(6H)-ones 15a-d, were designed and synthesized as topoisomerase IIα inhibitors with potential anticancer activity. The structure and their mechanistic pathway were discussed and confirmed based on spectral data and DFT calculations. Compounds 6a, 6c, 15b, 15c and 15d exhibited potent Topo II inhibitory activity at one-digit IC50 values (2.35 - 7.18 µM). Among the tested compounds, aminopyrazolopyrimidine derivatives 6a (IC50 = 3.44 µM) and 6c (IC50 = 2.35 µM) were comparable/ equipotent to Doxorubicin (IC50 = 2.71 µM) against Topo II. The most active compounds in Topo II assay were further investigated in vitro for their cytotoxic potential. The oxo-pyrazolopyrimidine derivative 15c; was the most potent possessing one-digit IC50 values (HCT116 IC50 = 2.32 ± 0.13 µM, MCF7 IC50 = 1.137 ± 0.06 µM). Compound 15c was two times more potent than Doxorubicin against MCF7 breast cancer cells. 15c exhibited a safety profile much better than that of Doxorubicin against non-cancerous cells. Compound 15c was also found to be a good apoptotic inducer. Moreover, docking result revealed well-fitting and proper orientation of 15c into Topo II-DNA complex.


Assuntos
Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
17.
Int J Mol Sci ; 23(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36012200

RESUMO

The uptake and distribution of doxorubicin in the MCF7 line of breast-cancer cells were monitored by Raman measurements. It was demonstrated that bioavailability of doxorubicin can be significantly enhanced by applying Congo red. To understand the mechanism of doxorubicin delivery by Congo red supramolecular carriers, additional monolayer measurements and molecular dynamics simulations on model membranes were undertaken. Acting as molecular scissors, Congo red particles cut doxorubicin aggregates and incorporated them into small-sized Congo red clusters. The mixed doxorubicin/Congo red clusters were adsorbed to the hydrophilic part of the model membrane. Such behavior promoted transfer through the membrane.


Assuntos
Vermelho Congo , Doxorrubicina , Vermelho Congo/farmacologia , Doxorrubicina/farmacologia , Excipientes , Interações Hidrofóbicas e Hidrofílicas
18.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012356

RESUMO

Novel nanocomposite materials based on Fe3O4 magnetic nanoparticles (MNPs) coated with silica and covalently modified by [(3-triethoxysilyl)propyl]succinic acid-polyethylene glycol (PEG 3000) conjugate, which provides a high level of doxorubicin (Dox) loading, were obtained. The efficiency of Dox desorption from the surface of nanomaterials under the action of an alternating magnetic field (AMF) in acidic and neutral media was evaluated. Their high cytotoxicity against tumor cells, as well as the drug release upon application of AMF, which leads to an increase in the cytotoxic effect, was demonstrated.


Assuntos
Nanopartículas de Magnetita , Nanopartículas , Neoplasias , Linhagem Celular , Doxorrubicina/farmacologia , Portadores de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Fenômenos Magnéticos , Polietilenoglicóis , Dióxido de Silício
19.
Int J Mol Sci ; 23(16)2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-36012610

RESUMO

Osteosarcoma (OSA) is the most common bone tumor in both humans and dogs and has a nearly ten-fold higher incidence in dogs than humans. Despite advances in the treatment of other cancers, the overall survival rates for OSA have stagnated for the past four decades. Therefore, there is a great need to identify novel and effective treatments. We screened a series of tyrosine kinase inhibitors and selected sorafenib, a multi-kinase inhibitor, for further evaluation alone and in combination with cisplatin, carboplatin, and doxorubicin on canine and human OSA cell lines. Our data point to synergistic effects when sorafenib is combined with doxorubicin, but not when combined with cisplatin or carboplatin, in both human and canine OSA. Based on current findings, clinical trials using a combination of doxorubicin and sorafenib in proof-of-concept studies in dogs are warranted. These studies can be carried out relatively quickly in dogs where case load is high and, in turn, provide useful data for the initiation of clinical trials in humans.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Doenças do Cão , Osteossarcoma , Apneia Obstrutiva do Sono , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/metabolismo , Carboplatina/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/veterinária , Apneia Obstrutiva do Sono/tratamento farmacológico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico
20.
PLoS One ; 17(8): e0272449, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35917304

RESUMO

BACKGROUND: Breast cancer chemotherapy with high dose alkylating agents is severely limited by their collateral toxicity to crucial normal tissues such as immune and gut cells. Taking advantage of the selective dependence of cancer cells on high glucose and combining glucose deprivation with these agents could produce therapeutic synergy. METHODS: In this study we examined the effect of glucose as well as its deprivation, and antagonism using the non-metabolized analogue 2-deoxy glucose, on the proliferation of several breast cancer cell lines MCF7, MDA-MB-231, YS1.2 and pII and one normal breast cell line, using the MTT assay. Motility was quantitatively assessed using the wound healing assay. Lactate, as the end product of anaerobic glucose metabolism, secreted into culture medium was measured by a biochemical assay. The effect of paclitaxel and doxorubicin on cell proliferation was tested in the absence and presence of low concentrations of glucose using MTT assay. RESULTS: In all cell lines, glucose supplementation enhanced while glucose deprivation reduced both their proliferation and motility. Lactate added to the medium could substitute for glucose. The inhibitory effects of paclitaxel and doxorubicin were significantly enhanced when glucose concentration was decreased in the culture medium, requiring 1000-fold lesser concentration to achieve a similar degree of inhibition to that seen in glucose-containing medium. CONCLUSION: Our data show that a synergy was obtained by combining paclitaxel and doxorubicin with glucose reduction to inhibit cancer cell growth, which in vivo, might be achieved by applying a carbohydrate-restricted diet during the limited phase of application of chemotherapy; this could permit a dose reduction of the cytotoxic agents, resulting in greater tolerance and lesser side effects.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Glucose/metabolismo , Humanos , Lactatos/farmacologia , Paclitaxel
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