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1.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204367

RESUMO

The constitutive expression or overactivation of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes results in aberrant metabolism of arachidonic acid and poor prognosis in melanoma. Our aim is to compare the in vitro effects of selective COX-1 (acetylsalicylic acid), COX-2 (meloxicam), 5-LOX (MK-886 and AA-861), 12-LOX (baicalein) and 15-LOX (PD-146176) inhibition in terms of proliferation (SRB assay), mitochondrial viability (MTT assay), caspase 3-7 activity (chemiluminescent assay), 2D antimigratory (scratch assay) and synthesis of eicosanoids (EIA) in the B16F10 cell line (single treatments). We also explore their combinatorial pharmacological space with dacarbazine and temozolomide (median effect method). Overall, our results with single treatments show a superior cytotoxic efficacy of selective LOX inhibitors over selective COX inhibitors against B16F10 cells. PD-146176 caused the strongest antiproliferation effect which was accompanied by cell cycle arrest in G1 phase and an >50-fold increase in caspases 3/7 activity. When the selected inhibitors are combined with the antineoplastic drugs, only meloxicam provides clear synergy, with LOX inhibitors mostly antagonizing. These apparent contradictions between single and combination treatments, together with some paradoxical effects observed in the biosynthesis of eicosanoids after FLAP inhibition in short term incubations, warrant further mechanistical in vitro and in vivo scrutiny.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Lipoxigenase/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase/química , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores de Lipoxigenase/química , Melanoma Experimental , Camundongos , Estrutura Molecular , Temozolomida/farmacologia
2.
Int J Nanomedicine ; 16: 2107-2121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33737808

RESUMO

Purpose: Although anti-programmed cell death protein 1 antibody (aPD1) immunotherapy and chemotherapy has made much progress in the treatment of melanoma, the efficacy still needs to be further improved. Methods: Cancer treatment has been greatly enhanced by the use of nanotechnology. Cancer cell membrane (CCM)-camouflaged nanoparticles have shown promising potential in tumor therapy due to their excellent homologous-targeting ability, long blood circulation and immune escape. This work presents a biocompatible and tumor acidic environmental responsive CCM-camouflaged mesoporous silica nanoparticle (CMSN) that is loaded with dacarbazine (DTIC) and combined with aPD1 to achieve better antitumor efficacy. Results: In vitro cell experiments demonstrated that DTIC@CMSN exhibits a better anti-tumor killing efficiency and a stronger ability to promote the apoptosis of tumor cells than free DTIC. In vivo antitumor results demonstrated that combination therapy of DTIC@CMSN chemotherapy and aPD1 immunotherapy remarkably suppress the melanoma growth and prolong survival time due to highly selective tumor killing, activation of tumor-specific T cells, and regulation of the immunosuppressive tumor microenvironment. In addition, safety evaluation studies of DTIC@CMSN also demonstrate their increased tumor accumulation and decreased systemic toxicity. Conclusion: This study provides a promising nano-platform for the combination of chemotherapy with immunotherapy, which is potentially useful for the treatment of melanoma.


Assuntos
Antineoplásicos/farmacologia , Membrana Celular/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Nanopartículas/química , Dióxido de Silício/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Porosidade , Eletricidade Estática
3.
Hematol Oncol ; 39(2): 185-195, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33462822

RESUMO

Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Estadiamento de Neoplasias/métodos , Vimblastina/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Brentuximab Vedotin/farmacologia , Dacarbazina/farmacologia , Doxorrubicina/farmacologia , Feminino , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vimblastina/farmacologia
4.
Neuro Oncol ; 23(6): 920-931, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33433610

RESUMO

BACKGROUND: Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% of patients) is associated with loss of MGMT expression (MGMT-) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT-mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly(ADP-ribose) polymerase (PARP). METHODS: MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O6-methylguanine (O6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ. RESULTS: We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT-expressing GBM. CONCLUSION: This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT-unmethylated GBM.


Assuntos
Glioblastoma , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Guanina/análogos & derivados , Humanos , Camundongos , Poli ADP Ribosilação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
5.
Drug Res (Stuttg) ; 70(12): 563-569, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33022719

RESUMO

BACKGROUND: Malignant melanoma is a common form of skin cancer that contains different cell types recognized by various cell surface markers. Dacarbazine-based combination chemotherapy is frequently used for the treatment of melanoma. Despite its potent anticancer properties, resistance to dacarbazine develops in malignant melanoma. Here, we aim to improve response to dacarbazine therapy by pretreatment with all-trans retinoic acid (ATRA) in CD117+ melanoma cells. METHODS: The CD117+ melanoma cells were sorted from A375 malignant melanoma cell line using magnetic-activated cell sorting (MACS). The cell viability was examined by cell proliferation assay (MTT). Apoptosis was determined by acridine orange/ ethidium bromide staining. Indeed, we performed flow cytometry to evaluate the cell cycle arrest. RESULTS: Here, the CD117+ melanoma cells were incubated with various concentrations of ATRA, dacarbazine, and their combination to determine IC50 values. We found that 20 µM ATRA treatment followed by dacarbazine was found to be more effective than dacarbazine alone. There was an indication that the combination of ATRA with dacarbazine (ATRA/dacarbazine) caused more apoptosis and necrosis in the melanoma cells (P<0.05). Furthermore, ATRA/dacarbazine treatment inhibited the cell at the G0/G1 phase, while dacarbazine alone inhibited the cells at S phase. CONCLUSION: Collectively, combined treatment with ATRA and dacarbazine induced more apoptosis and enhanced the cell cycle arrest of CD117+ melanoma cells. These results suggested that ATRA increased the sensitivity of melanoma cells to the effect of dacarbazine.


Assuntos
Dacarbazina/farmacologia , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Tretinoína/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Fase G1/efeitos dos fármacos , Humanos , Melanoma/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Neoplasias Cutâneas/metabolismo
6.
PLoS One ; 15(9): e0238238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881880

RESUMO

The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median survival of GB patients by only a few months over radiotherapy alone. While these survival gains could be partly attributed to radiosensitization, this benefit is greatly minimized in tumors expressing O6-methylguanine DNA methyltransferase (MGMT), which specifically reverses O6-methylguanine lesions. Theoretically, non-O6-methylguanine lesions (i.e., the N-methylpurine adducts), which represent up to 90% of TMZ-generated DNA adducts, could also contribute to radiosensitization. Unfortunately, at concentrations attainable in clinical practice, the alkylation capacity of TMZ cannot overwhelm the repair of N-methylpurine adducts to efficiently exploit these lesions. The current therapeutic application of TMZ therefore faces two main obstacles: (i) the stochastic presence of MGMT and (ii) a blunted radiosensitization potential at physiologic concentrations. To circumvent these limitations, we are developing a novel molecule called NEO212-a derivatization of TMZ generated by coupling TMZ to perillyl alcohol. Based on gas chromatography/mass spectrometry and high-performance liquid chromatography analyses, we determined that NEO212 had greater tumor cell uptake than TMZ. In mouse models, NEO212 was more efficient than TMZ at crossing the blood-brain barrier, preferentially accumulating in tumoral over normal brain tissue. Moreover, in vitro analyses with GB cell lines, including TMZ-resistant isogenic variants, revealed more potent cytotoxic and radiosensitizing activities for NEO212 at physiologic concentrations. Mechanistically, these advantages of NEO212 over TMZ could be attributed to its enhanced tumor uptake presumably leading to more extensive DNA alkylation at equivalent dosages which, ultimately, allows for N-methylpurine lesions to be better exploited for radiosensitization. This effect cannot be achieved with TMZ at clinically relevant concentrations and is independent of MGMT. Our findings establish NEO212 as a superior radiosensitizer and a potentially better alternative to TMZ for newly diagnosed GB patients, irrespective of their MGMT status.


Assuntos
Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Glioma/tratamento farmacológico , Radiossensibilizantes/uso terapêutico , Temozolomida/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dacarbazina/análise , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Cromatografia Gasosa-Espectrometria de Massas , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Radiossensibilizantes/análise , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Temozolomida/análise , Temozolomida/metabolismo , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Photochem Photobiol B ; 211: 111982, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32866820

RESUMO

Aberrant anti-cancer drug efflux mediated by membrane protein ABC transporters (ABCB5 and ABCG2) is thought to characterize melanoma heterogeneous chemoresistant populations, presumed to have unlimited proliferative and self-renewal abilities. Therefore, this study primarily aimed to investigate whether continuous exposure of melanoma cells to dacarbazine (DTIC) chemotherapeutic drug enriches cultures with therapy resistant cells. Thereafter, we sought to determine whether combining the genotoxic activity of DTIC with the oxidative insults of hypericin activated photodynamic therapy (HYP-PDT) could synergized to kill heterogenous chemoresistant melanoma populations. This study revealed that DTIC resistant (UCT Mel-1DTICR2) melanoma cells were less sensitive to all therapies than parental melanoma cells (UCT Mel-1), yet combination therapy was the most efficient. At the exception of DTIC treatment, both HYP-PDT and the combination therapy were effective in significantly reducing the Hoechst non-effluxing dye melanoma main populations (MP) compared to their side population (SP) counterparts. Likewise, HYP-PDT and combination therapy significantly reduced self-renewal capacity, increased expression of ABCB5 and ABCG2 transporters and differentially induced cell cycle arrest and cell death (apoptosis or necrosis) depending on the melanoma MP cell type. Collectively, combination therapy could synergistically reduce melanoma proliferative and clonogenic potential. However, further research is needed to decipher the cellular mechanisms underlying this resistance which would enable combination therapy to reach therapeutic fruition.


Assuntos
Antineoplásicos/química , Dacarbazina/química , Melanoma/terapia , Perileno/análogos & derivados , Fármacos Fotossensibilizantes/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Perileno/química , Perileno/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia
8.
Biomolecules ; 10(7)2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32650505

RESUMO

Malignant melanoma is a devastating disease. Because of its aggressiveness, it also serves as a model tumor for investigating novel therapeutic avenues. In recent years, scientific evidence has shown that cold atmospheric plasma (CAP) might be a promising modality in cancer therapy. In this study, we aimed to evaluate the effect of CAP generated by an argon plasma jet alone or in combination with dacarbazine (DAC) on melanoma cells in vitro and in vivo. The effects of the CAP on inducing lipid peroxidation and nitric oxide production were higher in B16 melanoma cells in comparison to non-malignant L929 cells. Assays on cell growth, apoptosis, and expression of genes related to, e.g., autophagic processes, showed CAP to have a substantial impact in melanoma cells while there were only minoreffects in L929 cells. In vivo, both CAP monotherapy and combination with DAC significantly decreased tumor growth. These results suggest that CAP not only selectively induces cell death in melanoma but also holds promises in combination with chemotherapy that might lead to improved tumor control.


Assuntos
Dacarbazina/administração & dosagem , Redes Reguladoras de Genes/efeitos dos fármacos , Melanoma/tratamento farmacológico , Gases em Plasma/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Dacarbazina/farmacologia , Tratamento Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Melanoma/genética , Melanoma/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Gases em Plasma/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biomater Sci ; 8(19): 5306-5316, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32573615

RESUMO

Glioma is the most aggressive primary malignant brain tumor. The eradication of the gliomas by performing neurosurgery has not been successful due to the diffuse nature of malignant gliomas. Temozolomide (TMZ) is the first-line agent in treating gliomas after surgery, and its therapeutic efficacy is limited mainly due to the high activity levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. Herein, we used an injectable matrix metalloproteinase (MMP) enzyme responsive hydrogel that loaded TMZ and O6-benzylamine (BG) (MGMT inhibitor) for eradicating residual TMZ-resistant gliomas after surgery. The hydrogels exhibited three features: (1) TMZ and BG could be encapsulated within the hydrophobic lamellae of the hydrogel to form Tm (TMZ + BG) hydrogels; (2) The hydrogels could release TMZ and BG in response to the high concentration of MMP enzymes after glioma surgery; (3) The hydrogels could increase local TMZ concentration and reduce side effects of BG. In vivo, the Tm (TMZ + BG) hydrogels inhibited the MGMT expression and sensitized TMZ-resistant glioma cells to TMZ. Moreover, the Tm (TMZ + BG) hydrogels effectively reduced the recurrence of TMZ-resistant glioma after surgery and significantly enhanced the efficiency of TMZ to inhibit glioma growth. Together, these data suggest that an MMP-responsive hydrogel is a promising localized drug delivery method to inhibit TMZ-resistant glioma recurrence after surgery.


Assuntos
Dacarbazina , Glioma , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioma/tratamento farmacológico , Humanos , Hidrogéis/farmacologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico
10.
Adv Drug Deliv Rev ; 153: 87-108, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497707

RESUMO

Nanoparticles offer new opportunities for the treatment of skin diseases. The barrier function of the skin poses a significant challenge for nanoparticles to permeate into the tissue, although the barrier is partially compromised in case of injury or inflammation, as in the case of skin cancer. This may facilitate the penetration of nanoparticles. Extensive research has gone into developing nanoparticles for topical delivery; however, relatively little progress has been made in translating them to the clinic for treating skin cancers. We summarize the types of skin cancers and practices in current clinical management. The review provides a comprehensive outlook of the various nanoparticle technologies tested for topical therapy of skin cancers and summarizes the obstacles that impede its progress from the bench-to-bedside. The review also aims to provide an understanding of the pathways that govern nanoparticle penetration into the skin and a critical analysis of the approaches used to study nanoparticle interactions within the tissue.


Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Administração Cutânea , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Ouro/química , Humanos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Absorção Cutânea/fisiologia , Fenômenos Fisiológicos da Pele
11.
Mol Biol (Mosk) ; 54(2): 267-277, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392196

RESUMO

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Dacarbazina/farmacologia , Melanoma Experimental/tratamento farmacológico , RNA/farmacologia , Animais , Imunoterapia , Fígado/efeitos dos fármacos , Camundongos , Baço/imunologia
12.
Mol Cell Biochem ; 469(1-2): 89-95, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32301060

RESUMO

Lysophosphatidic acid (LPA) signaling through LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties in cancer cells. Recently, we show that LPA2 expression is elevated by long-term cisplatin (CDDP) treatment in melanoma A375 cells. In the present study, we investigated whether LPA2-mediated signaling is involved in the modulation of chemoresistance in A375 cells. In cell survival assay, cells were treated with CDDP and dacarbazine (DTIC) every 24 h for 2 days. The cell survival rates to CDDP and DTIC were markedly increased by an LPA2 agonist, GRI-977143. To validate the effects of LPA2 on cell survival, LPA2 knockdown cells were generated from A375 cells. The cell survival rates elevated by GRI-977143 were suppressed by LPA2 knockdown. To evaluate the roles of LPA2-mediated signaling in cell survival, cells were pretreated with a Gi protein inhibitor, pertussis toxin (PTX). In the presence of GRI-977143, the cell survival rates to CDDP and DTIC were significantly lower in PTX-treated cells than in untreated cells. In addition, pretreatment of an adenylyl cyclase inhibitor, SQ22536, increased the cell survival of A375 cells treated with CDDP and DTIC. These results suggest that LPA2-mediated signaling plays an important role in the enhancement of chemoresistance of A375 cells treated with anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Lisofosfolipídeos/metabolismo , Melanoma/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/genética , Melanoma/genética , Toxina Pertussis/toxicidade , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
13.
Res Synth Methods ; 11(3): 443-456, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32125077

RESUMO

BACKGROUND: Network meta-analysis (NMA) of survival data with a multidimensional treatment effect has been introduced as an alternative to NMA based on the proportional hazards assumption. However, these flexible models have some limitations, such as the use of an approximate likelihood based on discrete hazards, rather than a likelihood for individual event times. The aim of this article is to overcome the limitations and present an alternative implementation of these flexible NMA models for time-to-event outcomes with a two-step approach. METHODS: First, for each arm of every randomised controlled trial (RCT) connected in the network of evidence, reconstructed patient data are fit to alternative survival distributions, including the exponential, Weibull, Gompertz, log-normal, and log-logistic. Next, for each distribution, its scale and shape parameters are included in a multivariate NMA to obtain time-varying estimates of relative treatment effects between competing interventions. RESULTS: An illustrative analysis is presented for a network of RCTs evaluating multiple interventions for advanced melanoma regarding overall survival. Alternative survival distributions were compared based on model fit criteria. Based on the log-logistic distribution, the difference in shape and scale parameters for each treatment versus dacarbazine (DTIC) was identified and the corresponding log hazard and survival curves were presented. CONCLUSIONS: The presented two-step NMA approach provides an evidence synthesis framework for time-to-event outcomes grounded in standard practice of parametric survival analysis. The method allows for a more transparent and efficient model selection process.


Assuntos
Interpretação Estatística de Dados , Melanoma/terapia , Análise Multivariada , Análise de Sobrevida , Dacarbazina/farmacologia , Humanos , Funções Verossimilhança , Melanoma/mortalidade , Metanálise em Rede , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Software , Fatores de Tempo , Resultado do Tratamento
14.
Melanoma Res ; 30(4): 426-428, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32141965

RESUMO

We observed several cases of hypotension associated with high-dose dacarbazine. We conducted a retrospective observational analysis of all patients treated with high-dose dacarbazine from January 2018 to August 2019 in Oscar Lambret Center, Lille, France. In our study, a total of 23 patients in outpatient care were analyzed, they underwent 57 treatment cycles. We observed 8 episodes of hypotension in 7 of the 23 consecutive treated patients (30.4%). We discuss herein several hypotheses explaining dacarbazine-induced hypotension. Dacarbazine high dose and administration methods seem to be the main causes of hypotension adverse events. Administration methods include administration duration, which should be above 2 hours, concomitant hydration with 500 ml 0.9% sodium chloride, and UV-resistant pump tube downstream the administration tree.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/uso terapêutico , Hipotensão/tratamento farmacológico , Doença Aguda , Antineoplásicos Alquilantes/farmacologia , Dacarbazina/farmacologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
15.
J Cell Mol Med ; 24(8): 4677-4686, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32181582

RESUMO

Glioma is a brain tumour that is often diagnosed, and temozolomide (TMZ) is a common chemotherapeutic drug used in glioma. Yet, resistance to TMZ is a chief hurdle towards curing the malignancy. The current work explores the pathways and involvement of miR-3116 in the TMZ resistance. miR-3116 and FGFR1 mRNA were quantified by real-time PCR in malignant samples and cell lines. Appropriate assays were designed for apoptosis, viability, the ability to form colonies and reporter assays to study the effects of the miR-3116 or FGFR1. The involvement of PI3K/AKT signalling was assessed using Western blotting. Tumorigenesis was evaluated in an appropriate xenograft mouse model in vivo. This work revealed that the levels of miR-3116 dipped in samples resistant to TMZ, while increased miR-3116 caused an inhibition of the tumour features mentioned above to hence augment TMZ sensitivity. miR-3116 was found to target FGFR1. When FGFR1 was overexpressed, resistance to TMZ was augmented and reversed the sensitivity caused by miR-3116. Our findings further confirmed PI3K/AKT signalling pathway is involved in this action. In conclusion, miR-3116 sensitizes glioma cells to TMZ through FGFR1 downregulation and the PI3K/AKT pathway inactivation. Our results provide a strategy to overcome TMZ resistance in glioma treatment.


Assuntos
Glioma/tratamento farmacológico , MicroRNAs/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Temozolomida/farmacologia , Animais , Apoptose/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Adv Drug Deliv Rev ; 153: 109-136, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113956

RESUMO

Skin cancer is a high burden disease with a high impact on global health. Conventional therapies have several drawbacks; thus, the development of effective therapies is required. In this context, nanotechnology approaches are an attractive strategy for cancer therapy because they enable the efficient delivery of drugs and other bioactive molecules to target tissues with low toxic effects. In this review, nanotechnological tools for skin cancer will be summarized and discussed. First, pathology and conventional therapies will be presented, followed by the challenges of skin cancer therapy. Then, the main features of developing efficient nanosystems will be discussed, and next, the most commonly used nanoparticles (NPs) described in the literature for skin cancer therapy will be presented. Subsequently, the use of NPs to deliver chemotherapeutics, immune and vaccine molecules and nucleic acids will be reviewed and discussed as will the combination of physical methods and NPs. Finally, multifunctional delivery systems to codeliver anticancer therapeutic agents containing or not surface functionalization will be summarized.


Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Administração Cutânea , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Ouro/química , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanotecnologia , Tamanho da Partícula , Absorção Cutânea/fisiologia , Fenômenos Fisiológicos da Pele , Propriedades de Superfície
17.
Anticancer Agents Med Chem ; 20(7): 887-896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32067621

RESUMO

BACKGROUND: Currently, most of the drugs used in clinical applications show their pharmacological influences by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug design for many diseases. OBJECTIVE: The current study aimed to contribute to this growing drug design field (i.e., medicine discovery and development) by analyzing enzyme-drug interactions. METHODS: For this reason, Paraoxonase-I (PON1) enzyme was purified from fresh human serum by using rapid chromatographic techniques. Additionally, the inhibition effects of some antineoplastic agents were researched on the PON1. RESULTS: The enzyme was obtained with a specific activity of 2603.57 EU/mg protein. IC50 values for pemetrexed disodium, irinotecan hydrochloride, dacarbazine, and azacitidine were determined to be 9.63µM, 30.13µM, 53.31µM, and 21.00mM, respectively. These agents found to strongly inhibit PON1, with Ki constants ranging from 8.29±1.47µM to 23.34±2.71mM. Dacarbazine and azacitidine showed non-competitive inhibition, while other drugs showed competitive inhibition. Furthermore, molecular docking was performed using maestro for these agents. Among these, irinotecan hydrochloride and pemetrexed disodium possess the binding energy of -5.46 and -8.43 kcal/mol, respectively. CONCLUSION: The interaction studies indicated that these agents with the PON1 possess binding affinity.


Assuntos
Antineoplásicos/farmacologia , Arildialquilfosfatase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/química , Arildialquilfosfatase/sangue , Arildialquilfosfatase/metabolismo , Azacitidina/química , Azacitidina/farmacologia , Dacarbazina/química , Dacarbazina/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Irinotecano/química , Irinotecano/farmacologia , Estrutura Molecular
18.
J R Soc Interface ; 17(162): 20190722, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31964274

RESUMO

Glioblastomas are among the most lethal cancers, with a 5 year survival rate below 25%. Temozolomide is typically used in glioblastoma treatment; however, the enzymes alkylpurine-DNA-N-glycosylase (APNG) and methylguanine-DNA-methyltransferase (MGMT) efficiently mediate the repair of DNA damage caused by temozolomide, reducing treatment efficacy. Consequently, APNG and MGMT inhibition has been proposed as a way of overcoming chemotherapy resistance. Here, we develop a mechanistic mathematical model that explicitly incorporates the effects of chemotherapy on tumour cells, including the processes of DNA damage induction, cell arrest and DNA repair. Our model is carefully parametrized and validated, and then used to virtually recreate the response of heteroclonal glioblastomas to dual treatment with temozolomide and inhibitors of APNG/MGMT. Using our mechanistic model, we identify four combination treatment strategies optimized by tumour cell phenotype, and isolate the strategy most likely to succeed in a pre-clinical and clinical setting. If confirmed in clinical trials, these strategies have the potential to offset chemotherapy resistance in patients with glioblastoma and improve overall survival.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico
19.
Fundam Clin Pharmacol ; 34(1): 20-31, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31410885

RESUMO

Malignant melanoma is a high aggressive malignancy in humans and causes 60-80% of deaths from skin cancer. Defect in an intrinsic pathway of apoptosis via overexpression of Mcl-1 is responsible for malignant melanoma development and progression, and also for resistance to chemotherapeutic agents. MIM1 is a specific low molecular Mcl-1 protein inhibitor that is able to induce Mcl-1-dependent cancer cells death. Here, we examined the effect of MIM1 as well as MIM1 and dacarbazine (DTIC) mixture on cell viability, apoptosis, and cell cycle progression in COLO829 melanoma cells. Cell viability was performed by the WST-1 assay. Analysis of apoptosis as well as cell cycle progression was determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrated that the MIM1 exhibited high cytotoxicity against melanotic melanoma cells and induced mitochondrial membrane breakdown, GSH depletion, and DNA fragmentation. Additionally, MIM1 enhanced the proapoptotic effect of DTIC toward melanoma cells; furthermore, a mixture of these drugs caused cell cycle arrest at G2/M phase in COLO829 cells. Taken together, these data provide, for the first time, evidence that a low molecular weight Mcl-1 inhibitor-MIM1 may be a promising agent with antitumor and proapoptotic properties toward melanoma cells.


Assuntos
Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/farmacologia , Glutationa/metabolismo , Humanos , Melanoma/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neoplasias Cutâneas/patologia
20.
Pathol Oncol Res ; 26(3): 1465-1474, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31432325

RESUMO

Mcl-1 is a potent antiapoptotic protein and amplifies frequently in many human cancer. Currently, it is considered that the extensively expressed of Mcl-1 protein in melanoma cells is associated with rapid tumor progression, poor prognosis and low chemosensitivity. Therefore, the antiapoptotic protein Mcl-1 could be considered as a potential target for malignant melanoma treatment. The aim of this study was to assess the effect of MIM1 a specific low molecular Mcl-1 protein inhibitor and mixture of MIM1 and dacarbazine on the viability, cell cycle progression and apoptosis induction in amelanotic C32 melanoma cells. The cytotoxic activity of MIM1 towards C32 melanoma cells was examined by the WST-1 test. The Mcl-1 protein level as a drug target in amelanotic melanoma cells was defined by Western blot analysis. Cell cycle progression, DNA fragmentation as well as GSH depletion were determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrate that the specific Mcl-1 protein inhibitor - MIM1 decreases cell viability and induce apoptosis (S-phase arrest, DNA fragmentation and redox imbalance) in amelanotic melanoma cells and intensify the proapoptotic properties of DTIC, as a result of interactions with Mcl-1 protein. Taken together, the presented data suggest that Mcl-1 protein is a an important target in malignant melanoma treatment and provide for the first time convincing evidence that MIM1, which inhibits Mcl-1 antiapoptotic protein is able to induce apoptosis and sensitize melanoma cells to alkylating agent.


Assuntos
Antineoplásicos/farmacologia , Melanoma Amelanótico/metabolismo , Melanoma Amelanótico/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dacarbazina/farmacologia , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Melanoma Amelanótico/genética , Proteínas Proto-Oncogênicas B-raf/genética
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