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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360968

RESUMO

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Dano ao DNA , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias/genética , Animais , Antineoplásicos/toxicidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cisplatino/toxicidade , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Free Radic Biol Med ; 174: 100-109, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34384867

RESUMO

Although cisplatin is an effective platinum-based anticancer drug against solid cancer, its availability is limited owing to its adverse side effects. Our study aimed to identify the potential relationship within cisplatin-induced multi-organ physiological changes and genetic factors associated with sex differences in nephrotoxicity susceptibility. To investigate this, mice received a single intraperitoneal injection of cisplatin. Cisplatin administration resulted in renal dysfunction, as evidenced by the elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine) and the degree of histopathological alterations. In particular, along with testicular damage and low testosterone levels, we also observed a decrease in male-specific (CYP3A2) or male-dominant (CYP2B1 and CYP3A1) CYP isoforms in the livers of rats with hepatotoxicity following cisplatin treatment, which may be associated with an imbalance in male hormone regulation caused by renal and testicular injury. Notably, we found that male rats were more susceptible to cisplatin-induced nephrotoxicity, as characterized by histopathological and biochemical analyses. Therefore, RNA sequencing was performed at baseline (pre-treatment) and at 48 h following cisplatin administration (post-treatment) to identify the genes associated with sex differences in nephrotoxicity susceptibility. Gap junctions, which play a role in replenishing damaged cells to maintain tissue homeostasis, and mismatch repair associated with a pathological apoptotic mechanism against cisplatin nephrotoxicity were significantly enriched only in males following cisplatin treatment. Moreover, among the 322 DEGs showing different basal expression patterns between males and females before cisplatin treatment, the male expressed high levels of genes, which are responsible for transmembrane transport and regulation of apoptotic process, pre-cisplatin treatment; additionally, genes involved in the PI3K-Akt signaling pathway and the oxidation-reduction process were significantly lower in males before cisplatin treatment. Collectively, our comprehensive findings provided valuable insight into the potential mechanisms of sex differences in cisplatin-induced nephrotoxicity susceptibility.


Assuntos
Antineoplásicos , Cisplatino , Animais , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Creatinina , Feminino , Rim , Masculino , Camundongos , Fosfatidilinositol 3-Quinases , Ratos , Caracteres Sexuais , Transcriptoma
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360955

RESUMO

Novel nontoxic derivatives of SN38 with favorable antineoplastic properties were characterized in water solution using NMR. The phenomena observed by NMR were linked to basic pharmacological properties, such as solubility, bioavailability, chemical and stereochemical stability, and binding to natural DNA oligomers through the terminal G-C base pair, which is commonly considered a biological target of Topo I inhibitors. Compound 1, with bulky substituents at both C5(R) and C20(S) on the same side of a camptothecin core, manifests self-association, whereas diastereomers 2, with bulky C5(S) and C20(S) substituents are mostly monomeric in solution. The stereogenic center at C5 is stable in water solution at pH 5-6. The compound with an (N-azetidinyl)methyl substituent at C9 can undergo the retro Mannich reaction after a prolonged time in water solution. Both diastereomers exhibit different abilities in terms of binding to DNA oligomers: compound 1 is strongly bound, whereas the binding of compound 2 is rather weak. Molecular modeling produced results consistent with NMR experiments. These complementary data allow linking of the observed phenomena in NMR experiments to basic preliminary information on the pharmacodynamic character of compounds and are essential for planning further development research.


Assuntos
Antineoplásicos/química , DNA/química , Irinotecano/análogos & derivados , Simulação de Acoplamento Molecular , Inibidores da Topoisomerase I/química , Antineoplásicos/toxicidade , Irinotecano/toxicidade , Inibidores da Topoisomerase I/toxicidade
4.
Toxicology ; 459: 152852, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34246718

RESUMO

Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.


Assuntos
Envelhecimento/efeitos dos fármacos , Antibióticos Antineoplásicos/toxicidade , Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitoxantrona/toxicidade , Proteoma/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , Masculino , Camundongos , Mitocôndrias Cardíacas/enzimologia , Miócitos Cardíacos/patologia , Tamanho do Órgão/efeitos dos fármacos
5.
Toxicology ; 459: 152853, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252480

RESUMO

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Alcaloides de Berberina/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Gânglios Espinais/metabolismo , Mitocôndrias/metabolismo , Oxaliplatina/farmacocinética , Oxaliplatina/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Ratos , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo
6.
J Sex Med ; 18(8): 1337-1345, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34281797

RESUMO

BACKGROUND: Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED). AIM: To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP). METHODS: Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9-10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation- and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22phox, interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student's t-test. OUTCOMES: The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels. CLINICAL TRANSLATION: The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors. STRENGTHS AND LIMITATIONS: Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence. CONCLUSIONS: L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction. Kataoka T, Mori T, Suzuki J, et al. Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction. J Sex Med 2021;18:1337-1345.


Assuntos
Antineoplásicos , Disfunção Erétil , Animais , Antineoplásicos/toxicidade , Modelos Animais de Doenças , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Óxido Nítrico Sintase Tipo III , Oxaliplatina/uso terapêutico , Ereção Peniana , Pênis , Ratos , Ratos Wistar
7.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299130

RESUMO

Although cisplatin is one of most effective chemotherapeutic drugs that is widely used to treat various types of cancer, it can cause undesirable damage in immune cells and normal tissue because of its strong cytotoxicity and non-selectivity. This study was conducted to investigate the cytoprotective effects of Cudrania tricuspidata fruit-derived polysaccharides (CTPS) against cisplatin-induced cytotoxicity in macrophages, lung cancer cell lines, and a mouse model, and to explore the possibility of application of CTPS as a supplement for anticancer therapy. Both cisplatin alone and cisplatin with CTPS induced a significant cytotoxicity in A549 and H460 lung cancer cells, whereas cytotoxicity was suppressed by CTPS in cisplatin-treated RAW264.7 cells. CTPS significantly attenuated the apoptotic and necrotic population, as well as cell penetration in cisplatin-treated RAW264.7 cells, which ultimately inhibited the upregulation of Bcl-2-associated X protein (Bax), cytosolic cytochrome c, poly (adenosine diphosphateribose) polymerase (PARP) cleavage, and caspases-3, -8, and -9, and the downregulation of B cell lymphoma-2 (Bcl-2). The CTPS-induced cytoprotective action was mediated with a reduction in reactive oxygen species production and mitochondrial transmembrane potential loss in cisplatin-treated RAW264.7 cells. In agreement with the results obtained above, CTPS induced the attenuation of cell damage in cisplatin-treated bone marrow-derived macrophages (primary cells). In in vivo studies, CTPS significantly inhibited metastatic colonies and bodyweight loss as well as immunotoxicity in splenic T cells compared to the cisplatin-treated group in lung metastasis-induced mice. Furthermore, CTPS decreased the level of CRE and BUN in serum. In summation, these results suggest that CTPS-induced cytoprotective action may play a role in alleviating the side effects induced by chemotherapeutic drugs.


Assuntos
Cisplatino/toxicidade , Frutas/química , Macrófagos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Moraceae/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antineoplásicos/toxicidade , Apoptose , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Macrófagos/patologia , Melanoma Experimental/induzido quimicamente , Melanoma Experimental/patologia , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Substâncias Protetoras/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
EBioMedicine ; 69: 103456, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34233258

RESUMO

BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. METHODS: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. FINDINGS: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. INTERPRETATION: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity. FUNDING: NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.


Assuntos
Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Ferroptose , Cardiopatias/genética , Miócitos Cardíacos/efeitos dos fármacos , Ribonucleoproteínas/genética , Animais , Cardiotoxicidade/genética , Linhagem Celular , Células Cultivadas , Cardiopatias/etiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Ratos
9.
J Nanosci Nanotechnol ; 21(12): 6143-6150, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229815

RESUMO

Ionic liquids are an interesting class of materials that have recently been utilized as chemotherapeutic agents in cancer therapy. Aniline blue, a commonly used biological staining agent, was used as a counter ion to trihexyltetradecylphosphonium, a known cytotoxic cation. A facile, single step ion exchange reaction was performed to synthesize a fluorescent ionic liquid, trihexyltetradecylphosphonium aniline blue. Aqueous nanoparticles of this hydrophobic ionic liquid were prepared using reprecipitationmethod. The newly synthesized ionic liquid and subsequent nanoparticles were characterized using various spectroscopic techniques. Transmission electron microscopy and zeta potential measurements were performed to characterize the nanoparticles' morphology and surface charge. The photophysical properties of the nanoparticles and the parent aniline blue compound were studied using absorption and fluorescence spectroscopy. Cell viability studies were conducted to investigate the cytotoxicity of the newly developed trihexyltetradecylphosphonium aniline blue nanoparticles in human breast epithelial cancer cell line (MCF-7) and its corresponding normal epithelial cell line (MCF-10A) in vitro. The results revealed that the synthesized ionic nanomedicines were more cytotoxic (lower IC50) than the parent chemotherapeutic compound in MCF-7 cells. Nanoparticles of the synthesized ionic liquid were also shown to be more stable in both aqueous and cellular media and more selective than parent compounds towards cancer cells.


Assuntos
Antineoplásicos , Líquidos Iônicos , Nanopartículas , Compostos de Anilina , Antineoplásicos/toxicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Líquidos Iônicos/toxicidade
10.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206985

RESUMO

Microbial conjugation studies of licochalcones (1-4) and xanthohumol (5) were performed by using the fungi Mucor hiemalis and Absidia coerulea. As a result, one new glucosylated metabolite was produced by M. hiemalis whereas four new and three known sulfated metabolites were obtained by transformation with A. coerulea. Chemical structures of all the metabolites were elucidated on the basis of 1D-, 2D-NMR and mass spectroscopic data analyses. These results could contribute to a better understanding of the metabolic fates of licochalcones and xanthohumol in mammalian systems. Although licochalcone A 4'-sulfate (7) showed less cytotoxic activity against human cancer cell lines compared to its substrate licochalcone A, its activity was fairly retained with the IC50 values in the range of 27.35-43.07 µM.


Assuntos
Absidia/metabolismo , Chalconas/química , Flavonoides/química , Mucor/metabolismo , Propiofenonas/química , Células A549 , Absidia/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chalconas/metabolismo , Chalconas/toxicidade , Flavonoides/metabolismo , Flavonoides/toxicidade , Humanos , Células MCF-7 , Metaboloma , Mucor/química , Propiofenonas/metabolismo , Propiofenonas/toxicidade
11.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208184

RESUMO

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.


Assuntos
Cloridrato de Duloxetina/farmacologia , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Neuralgia/tratamento farmacológico , Oxaliplatina/toxicidade , Limiar da Dor/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Antibacterianos/farmacologia , Antineoplásicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Masculino , Camundongos , Microglia/fisiologia , Neuralgia/induzido quimicamente , Neuralgia/patologia
12.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201218

RESUMO

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.


Assuntos
Antineoplásicos/toxicidade , Blefarite/patologia , Córnea/irrigação sanguínea , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Inflamação/patologia , Aparelho Lacrimal/patologia , Animais , Blefarite/etiologia , Blefarite/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Aparelho Lacrimal/metabolismo , Linfangiogênese , Camundongos , Camundongos Endogâmicos C57BL
13.
Life Sci ; 281: 119804, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34229010

RESUMO

AIMS: Oxaliplatin is an effective anti-cancer platinum-based chemotherapy drug which can cause severe chronic neuropathy, but the molecular mechanism underlying this adverse effect is still unclear. Opa interacting protein 5 (OIP5) is a member of the cancer/testis antigen (CTA) family and is involved in a variety of cancers. Studies have shown that Raf1, which is a serine/threonine-protein kinase, can directly combine with OIP5 to promote its expression. Whether Raf1 and OIP5 can participate in oxaliplatin-induced neuropathic pain has not been reported. MAIN METHODS: In this study, the oxaliplatin-induced neuropathic pain model was prepared by intraperitoneal injection of oxaliplatin. OIP5 and Raf1 were knocked down by intrathecal injection of siRNA against Raf1 and OIP5 (siRaf1, siOIP5). Von Frey fiber and acetone were used to detect pain behavior, and western blot was used to detect the protein expression changes of OIP5 and Raf1 in the dorsal root ganglion (DRG). KEY FINDINGS: The expression levels of p-Raf1 and OIP5 were increased in DRGs of oxaliplatin-induced neuropathic pain rats. Intrathecal administration of siOIP5 to inhibit the expression of OIP5 not only effectively alleviated oxaliplatin-induced mechanical allodynia and cold hyperalgesia, but also decreased the protein expression of Raf1. Intrathecal administration of siRaf1 inhibited the expression of OIP5 and attenuated oxaliplatin-induced neuropathic pain. SIGNIFICANCE: This study confirmed that Raf1 interacts with OIP5 to participate in oxaliplatin-induced neuropathic pain. The restricted expression of OIP5 in normal tissues may make it an ideal drug target for the treatment of oxaliplatin-induced neuropathic pain.


Assuntos
Antineoplásicos/toxicidade , Proteínas de Ciclo Celular/metabolismo , Neuralgia/induzido quimicamente , Oxaliplatina/toxicidade , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Neuralgia/metabolismo , Células PC12 , Ligação Proteica , Ratos , Ratos Sprague-Dawley
14.
Neurology ; 97(7): e660-e672, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34078718

RESUMO

BACKGROUND AND OBJECTIVE: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. METHODS: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. RESULTS: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. CONCLUSIONS: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.


Assuntos
Antineoplásicos/toxicidade , Técnicas de Diagnóstico Neurológico/normas , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Psicometria/normas , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Síndromes Neurotóxicas/etiologia , Enfermeiras e Enfermeiros , Pacientes , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Médicos , Estudos Prospectivos , Psicometria/instrumentação , Adulto Jovem
15.
DNA Cell Biol ; 40(8): 1101-1111, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34156283

RESUMO

Chronic myeloid leukemia (CML) is characterized by the formation of the BCR-ABL fusion gene. The BCR-ABL protein leads to an increased level of reactive oxygen species, which is a major cause of endogenous DNA double-strand breaks (DSBs). CML cells are prone to rely on a highly mutagenic alternative end-joining (Alt-EJ) pathway to cope with enhanced DSBs, which aggravates chromosomal instability. Hence, targeting dysregulated DNA repair proteins provides new insights into cancer treatment. In this study, we discovered the abnormal upregulation of Flap endonuclease 1 (FEN1) in CML, as well as FEN1's participation in the error-prone Alt-EJ repair pathway and its interplay with DNA Ligase1 and proliferating cell nuclear antigen in DSB repair. Knockdown of FEN1 by shRNA not only inhibited the proliferation and induced apoptosis but also enhanced the efficacy of imatinib (IM) in drug-resistant CML cell K562/G01. Moreover, excessive DSB accumulation was detected after FEN1 inhibition. In summary, our results demonstrated that FEN1 is a promising therapeutic target in CML treatment. This work extends the understanding of regulating abnormal DSB repair for cancer treatment.


Assuntos
Proliferação de Células , Reparo do DNA por Junção de Extremidades , Endonucleases Flap/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Antineoplásicos/toxicidade , Apoptose , Células Cultivadas , DNA Ligase Dependente de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos , Endonucleases Flap/metabolismo , Células HEK293 , Humanos , Mesilato de Imatinib/toxicidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Células THP-1
16.
Chem Commun (Camb) ; 57(56): 6919-6922, 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34155490

RESUMO

We demonstrate an intrinsic antitumor effect of polymer nanoparticles (P-NPs), which could re-program tumor-associated macrophages to pro-inflammatory phenotype. The intrinsic effect of P-NPs on macrophage repolarization and its combination with other therapies provide new ideas for drug delivery, macrophage regulation and immunotherapy in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Maleatos/farmacologia , Nanopartículas/química , Poliestirenos/farmacologia , Polivinil/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Maleatos/química , Maleatos/toxicidade , Camundongos , Nanopartículas/toxicidade , Poliestirenos/química , Poliestirenos/toxicidade , Polivinil/química , Polivinil/toxicidade
17.
ACS Appl Mater Interfaces ; 13(24): 27934-27944, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34101408

RESUMO

Due to conventional photodynamic therapy encountering serious problems of phototoxicity and low tissue-penetrating depth of light, other dynamic therapy-based therapeutic methods such as sonodynamic therapy (SDT) are expected to be developed. To improve the therapeutic response to SDT, more effective sonosensitizers are imperative. In this study, a novel water-soluble iridium(III)-porphyrin sonosensitizer (IrTMPPS) was synthesized and used for SDT. IrTMPPS generated ample singlet oxygen (1O2) under US irradiation and especially showed distinguished US-activatable abilities at more than 10 cm deep-tissue depths. Interestingly, under US irradiation, IrTMPPS sonocatalytically oxidized intracellular NADH, which would enhance SDT efficiency by breaking the redox balance in the tumor. Moreover, IrTMPPS displayed great sonocytotoxicity toward various cancer cells, and in vivo experiments demonstrated efficient tumor inhibition and anti-metastasis to the lungs in the presence of IrTMPPS and US irradiation. This report gives a novel idea of metal-based sonosensitizers for sonotherapy by fully taking advantage of non-invasiveness, water solubility, and deep tumor therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Porfirinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Irídio/química , Irídio/uso terapêutico , Irídio/toxicidade , Camundongos , NAD/química , NAD/metabolismo , Neoplasias/patologia , Oxirredução , Porfirinas/síntese química , Porfirinas/toxicidade , Radiossensibilizantes/síntese química , Radiossensibilizantes/toxicidade , Oxigênio Singlete/metabolismo , Ondas Ultrassônicas , Peixe-Zebra
18.
ACS Appl Mater Interfaces ; 13(24): 27963-27971, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34110773

RESUMO

1T-phase transition-metal dichalcogenides (TMDs) nanomaterials are one type of emerging and promising near-infrared II (NIR-II) photothermal agents (PTAs) derived from their distinct metallic electronic structure, but it is still challenging to synthesize these nanomaterials. Herein, PdTe2 nanoparticles (PTNs) with a 1T crystal symmetry and around 50 nm in size are prepared by an electrochemical exfoliation method, and the corresponding photothermal performances irradiated under a NIR-II laser have been explored. The encapsulation of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) endows PTNs with water solubility, enhanced photothermal stability, and high biocompatibility. Notably, PTN/DSPE-PEG displays a potent absorbance through the NIR-II zone and considerable photothermal conversion efficiency, which is up to 68% when irradiated with a 1060 nm laser. With these unique photothermal properties, excellent in vitro and in vivo tumor inhibition effects of PTN/DSPE-PEG have been achieved under the irradiation of a NIR-II (1060 nm) laser without visible toxicity to normal tissues, suggesting that it is an efficient NIR-II photothermal nanoagent.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Feminino , Interações Hidrofóbicas e Hidrofílicas , Raios Infravermelhos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Nanopartículas Metálicas/toxicidade , Camundongos Endogâmicos BALB C , Paládio/química , Paládio/efeitos da radiação , Paládio/uso terapêutico , Paládio/toxicidade , Fosfatidiletanolaminas/química , Terapia Fototérmica , Polietilenoglicóis/química , Telúrio/química , Telúrio/efeitos da radiação , Telúrio/uso terapêutico , Telúrio/toxicidade
19.
Toxicol Appl Pharmacol ; 426: 115618, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126112

RESUMO

WHO suggests that colon cancer incidences are rising steadily, propelling researchers to search for novel chemotherapeutic options. Metal-based chemotherapy is a potential forte to explore ruthenium-based complexes, exhibiting the capability to influence a variety of cellular targets. We discovered the chemotherapeutic effects of ruthenium-rifampicin complex on HT-29 and HCT-116 human colorectal cell lines and on a chemically developed murine colorectal cancer model. Complex was synthesized and characterized by analytical techniques and evaluation of antioxidant potential along with DNA binding capabilities. The complex minimizes cellular propagation and initiates apoptotic events in the colon cancer cell lines of HT-29 and HCT-116. The results of the in vivo study suggest that the complex has been successful in minimizing the wide spectrum of aberrant crypt foci and hyperplastic lesions, as well as encouraging elevated amounts of CAT, SOD and glutathione. Along with that, p53 could be modulated by the ruthenium-rifampicin complex to interfere with apoptosis in colon carcinoma, initiated by the intrinsic apoptotic trail facilitated through Bcl2 and Bax, thus controlling the Akt/mTOR/VEGF pathway coupled through the WNT/ß-catenin trail. Ruthenium-rifampicin chemotherapy could interrupt, retract or interrupt the progression of colorectal cancer through modifying intrinsic apoptosis including the antiangiogenic pathway, thereby achieving the function of a potential contender in chemotherapy in the near future.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Rifampina/uso terapêutico , Compostos de Rutênio/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Combinação de Medicamentos , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Rifampina/farmacologia , Rifampina/toxicidade , Compostos de Rutênio/farmacologia , Compostos de Rutênio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Toxins (Basel) ; 13(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064873

RESUMO

Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.


Assuntos
Glicosídeos Cardíacos/farmacologia , Terapia de Alvo Molecular , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Glicosídeos Cardíacos/biossíntese , Glicosídeos Cardíacos/toxicidade , Bovinos , Digitoxina/farmacologia , Digitoxina/toxicidade , Digoxina/farmacologia , Digoxina/toxicidade , Humanos , Neoplasias/tratamento farmacológico , Ouabaína/farmacologia , Ouabaína/toxicidade
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