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1.
Ann Palliat Med ; 10(8): 9025-9038, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488389

RESUMO

BACKGROUND: Cisplatin has been a vital drug used for tumor treatment because of its excellent effect on numerous malignant solid cancers. Nonetheless, its nephrotoxicity is non-negligible in clinical practice. This study aims to provide a new understanding of the molecular mechanism of transient receptor potential ankyrin 1 (TRPA1) in cisplatin-induced renal apoptosis. METHODS: We evaluated the effect on apoptosis, TRPA1 expression, and intracellular calcium concentration of human kidney 2 (HK-2) cells induced by diamminedichloroplatinum (DDP). Additionally, we also assessed DDP-induced apoptosis, the expression of Bax, caspase3, cleaved-cas3, p53, Bcl-2 and intracellular calcium concentration combined with HC-030031 and/or pifithrin-α. The effect of FK506 on apoptosis of HK-2 cells induced by DDP and the expression of the nuclear factor of activated T cells (NFAT) protein treated with HC-030031, pifithrin-α, and/or FK506 were also explored. RESULTS: The results showed that apoptosis, TRPA1 expression, and intracellular calcium concentration of HK-2 cell induced by DDP were enhanced in a dose-dependent manner. HC-030031 and pifithrin-α relieved apoptosis, and intracellular calcium concentration and the expression of NFAT and phospho-NFAT (p-NFAT) were induced by DDP. HC-030031 combined with pifithrin-α further aggravated the above-mentioned tendency, including relieved apoptosis, intracellular calcium concentration, and NFAT and p-NFAT expression. HC-030031 and FK506 decelerated the apoptosis, and NFAT and p-NFAT expression of HK-2 cells was induced by DDP, while simultaneous treatment with HC-030031 and FK506 further decreased apoptosis and protein expression. However, the expression of Bcl-2 increased when HC-030031, pifithrin-α, or FK506 was used alone, and HC-030031 combined with pifithrin-α or FK506 further improved the expression of Bcl-2. CONCLUSIONS: TRPA1 mediates cisplatin-induced apoptosis in renal tubular cells via the calcineurin-nuclear factor of activated T-cells-p53 signaling pathway.


Assuntos
Apoptose , Cálcio , Cisplatino , Túbulos Renais/citologia , Transdução de Sinais , Canal de Cátion TRPA1/metabolismo , Linhagem Celular , Cisplatino/farmacologia , Humanos
2.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445277

RESUMO

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino , Antagonismo de Drogas , Inibidores de Histona Desacetilases/farmacologia , Modelos Biológicos , Naftalenos , Pirimidinonas , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Feminino , Humanos , Células MCF-7 , Naftalenos/antagonistas & inibidores , Naftalenos/farmacologia , Pirimidinonas/antagonistas & inibidores , Pirimidinonas/farmacologia
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360933

RESUMO

Cisplatin is among the most widely used anticancer drugs used in the treatment of several malignancies, including oral cancer. However, cisplatin treatment often promotes chemical resistance, subsequently causing treatment failure. Several studies have shown that epidermal growth factor receptors (EGFRs) play a variety of roles in cancer progression and overcoming cisplatin resistance. Therefore, this study focused on EGFR inhibitors used in novel targeted therapies as a method to overcome this resistance. We herein aimed to determine whether the combined effects of cisplatin and cetuximab could enhance cisplatin sensitivity by inhibiting the epithelial-to-mesenchymal transition (EMT) process in cisplatin-resistant cells. In vitro analyses of three cisplatin-resistant oral squamous cell carcinoma cells, which included cell proliferation assay, combination index calculation, cell cytotoxicity assay, live/dead cell count assay, Western blot assay, propidium iodide staining assay, scratch assay, and qRT-PCR assay were then conducted. Our results showed that a cisplatin/cetuximab combination treatment inhibited cell proliferation, cell motility, and N-cadherin protein expression but induced E-cadherin and claudin-1 protein expression. Although the combination of cisplatin and cetuximab did not induce apoptosis of cisplatin-resistant cells, it may be useful in treating oral cancer patients with cisplatin resistance given that it controls cell motility and EMT-related proteins.


Assuntos
Cetuximab/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Combinação de Medicamentos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos
4.
Molecules ; 26(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34443328

RESUMO

Cisplatin is widely employed as a first-line chemotherapeutic agent for many solid tumors, including malignant pleural mesothelioma (MPM). However, its clinical use is limited by heavy side effects and acquired resistance, the latter being mainly related to enhanced DNA repair. Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPis) have been carried out, with the hope that such combinations might lead to improved therapeutic efficacy against tumors. Here, the synthesis and efficacy in reducing MPM cell viability of four cisplatin-based Pt(IV) prodrugs containing the PARPi 3-aminobenzamide (3-ABA) fragment are described. The most promising conjugate is more effective than cisplatin or cisplatin/3-ABA combination, administered in equimolar doses, in inhibiting PARP-1 activity and inducing apoptosis in BRCA1/2 wild type MPM cells, grown as monolayer or as multicellular spheroids.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/química , Cisplatino/farmacologia , Mesotelioma Maligno/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
5.
Nat Commun ; 12(1): 4960, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400618

RESUMO

Agonists of glucocorticoid receptor (GR) are frequently given to cancer patients with platinum-containing chemotherapy to reduce inflammation, but how GR influences tumor growth in response to platinum-based chemotherapy such as cisplatin through inflammation-independent signaling remains largely unclear. Combined genomics and transcription factor profiling reveal that MAST1, a critical platinum resistance factor that reprograms the MAPK pathway, is upregulated upon cisplatin exposure through activated transcription factor GR. Mechanistically, cisplatin binds to C622 in GR and recruits GR to the nucleus for its activation, which induces MAST1 expression and consequently reactivates MEK signaling. GR nuclear translocation and MAST1 upregulation coordinately occur in patient tumors collected after platinum treatment, and align with patient treatment resistance. Co-treatment with dexamethasone and cisplatin restores cisplatin-resistant tumor growth, whereas addition of the MAST1 inhibitor lestaurtinib abrogates tumor growth while preserving the inhibitory effect of dexamethasone on inflammation in vivo. These findings not only provide insights into the underlying mechanism of GR in cisplatin resistance but also offer an effective alternative therapeutic strategy to improve the clinical outcome of patients receiving platinum-based chemotherapy with GR agonists.


Assuntos
Cisplatino/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Platina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular , Sobrevivência Celular , Citocinas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Braz J Med Biol Res ; 54(10): e11156, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378676

RESUMO

The objective of this study was to investigate the effect of human esophageal fibroblast-derived exosomal miR-21 on cisplatin sensitivity against esophageal squamous EC9706 cells. EC9706 cells were co-cultured indirectly with human esophageal fibroblasts (HEF) or miR-21 mimics transfected-HEF in the transwell system. The exosomes in HEF-culture conditioned medium were extracted by differential ultracentrifugation. EC9706 cells were co-cultured with HEF-derived exosomes directly. The cisplatin sensitivity against EC9706 cells was revealed via half maximal inhibitory concentration (IC50) values using MTT assay. The expressions of miR-21, programmed cell death 4 (PDCD4) mRNA, and gene of phosphate and tension homology deleted on chromosome ten (PTEN) mRNA were determined by qRT-PCR. The changes of the protein level were detected using western blot assay. IC50 values of cisplatin against EC9706 cells were increased after EC9706 cells were co-cultured with either HEF or exosomes derived from miR-21 mimics-transfected HEF. Following the increased level of miR-21, the mRNA expression and protein levels of PTEN and PDCD4 were decreased in EC9706 cells. The cisplatin sensitivity to EC9706 cells was reduced by HEF-derived exosomal miR-21 through targeting PTEN and PDCD4. This study suggested that non-tumor cells in the tumor micro-environment increased the tumor anti-chemotherapy effects through their exosomes.


Assuntos
Carcinoma , Neoplasias Esofágicas , MicroRNAs , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Fibroblastos/metabolismo , Humanos , MicroRNAs/genética , Proteínas de Ligação a RNA , Microambiente Tumoral
7.
Comput Biol Med ; 135: 104640, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34261004

RESUMO

Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.


Assuntos
Antineoplásicos , Diabetes Mellitus Tipo 2 , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Proteínas de Choque Térmico/farmacologia , Proteínas de Choque Térmico/uso terapêutico , Humanos , Insulina/farmacologia , Transdução de Sinais
8.
Biol Res ; 54(1): 22, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321115

RESUMO

BACKGROUND: Accumulated evidence demonstrates cisplatin, a recommended chemotherapy, modulating pro-survival autophagic response that contributes to treatment failure in lung cancer patients. However, distinct mechanisms involved in cisplatin-induced autophagy in human lung cancer cells are still unclear. RESULTS: Herein, role of autophagy in cisplatin resistance was indicated by a decreased cell viability and increased apoptosis in lung cancer H460 cells pre-incubated with wortmannin, an autophagy inhibitor, prior to treatment with 50 µM cisplatin for 24 h. The elevated level of hydroxyl radicals detected via flow-cytometry corresponded to autophagic response, as evidenced by the formation of autophagosomes and autolysosomes in cisplatin-treated cells. Interestingly, apoptosis resistance, autophagosome formation, and the alteration of the autophagic markers, LC3-II/LC3-I and p62, as well as autophagy-regulating proteins Atg7 and Atg3, induced by cisplatin was abrogated by pretreatment of H460 cells with deferoxamine, a specific hydroxyl radical scavenger. The modulations in autophagic response were also indicated in the cells treated with hydroxyl radicals generated via Fenton reaction, and likewise inhibited by pretreatment with deferoxamine. CONCLUSIONS: In summary, the possible role of hydroxyl radicals as a key mediator in the autophagic response to cisplatin treatment, which was firstly revealed in this study would benefit for the further development of novel therapies for lung cancer.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Autofagia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Radical Hidroxila/farmacologia , Radical Hidroxila/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico
9.
Aging (Albany NY) ; 13(13): 17407-17427, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232919

RESUMO

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.


Assuntos
Antinematódeos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mebendazol/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Cisplatino/uso terapêutico , Reposicionamento de Medicamentos , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaio Tumoral de Célula-Tronco , Cicatrização , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Pharm ; 606: 120899, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34324990

RESUMO

We successfully prepared and characterized a hyaluronic acid- and folic acid-based hydrogel for the delivery of cisplatin (GEL-CIS) with the aim to induce specific and efficient incorporation of CIS into ovarian cancer (OC) cells, improve its antineoplastic effect and avoid CIS-resistance. The slow and controlled release of the drug from the polymeric network and its swelling degree at physiologic pH suggested its suitability for CIS delivery in OC. We compared here the effects of pure CIS to that of GEL-CIS on human OC cell lines, either wild type or CIS-resistant, in basal conditions and in the presence of macrophage-derived conditioned medium, mimicking the action of tumor-associated macrophages in vivo. GEL-CIS inhibited OC cell growth and migration more efficiently than pure CIS and modulated the expression of proteins involved in the Epithelial Mesenchymal Transition, a process playing a key role in OC metastatic spread and resistance to CIS.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Ácido Fólico/farmacologia , Humanos , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico
11.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299199

RESUMO

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Platina/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Cisplatino/farmacologia , Complexos de Coordenação/química , Resistencia a Medicamentos Antineoplásicos , Flavonoides/química , Humanos , Ligantes , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Platina/química , Compostos de Rutênio/química , Células Tumorais Cultivadas
12.
Int J Biol Macromol ; 185: 604-619, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34216662

RESUMO

Hepatic cancer is one of the most widespread maladies worldwide that requires urgent therapies and thus reliable means for testing anti-cancer drugs. The switch from two-dimensional (2D) to three-dimensional (3D) cell cultures produced an improvement in the in vitro outcomes for testing anti-cancer drugs. We aimed to develop a novel hyaluronic acid (HA)-based 3D cell model of human hepatocellular carcinoma (HepG2 cells) for drug testing and to assess comparatively in 3D vs. 2D, the cytotoxicity and the apoptotic response to the anti-tumor agent, cisplatin. The 3D model was developed by seeding HepG2 cells in a HA/poly(methylvinylether-alt-maleic acid) (HA3P50)-based scaffold. Compared to 2D, the cells grown in the HA3P50 scaffold proliferate into larger-cellular aggregates that exhibit liver-like functions by controlling the release of hepatocyte-specific biomarkers (albumin, urea, bile acids, transaminases) and the synthesis of cytochrome-P450 (CYP)7A1 enzyme. Also, growing the cells in the scaffold sensitize the hepatocytes to the anti-tumor effect of cisplatin, by a mechanism involving the activation of ERK/p38α-MAPK and dysregulation of NF-kB/STAT3/Bcl-2 pathways. In conclusion, the newly developed HA-based 3D model is suitable for chemotherapeutic drug testing on hepatocellular carcinoma. Moreover, the system can be adapted and employed as experimental platform functioning as a proper tissue/tumor surrogate.


Assuntos
Materiais Biomiméticos/química , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Ácido Hialurônico/química , Neoplasias Hepáticas/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/metabolismo , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Tecidos Suporte
13.
Mol Cell ; 81(15): 3128-3144.e7, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216544

RESUMO

Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions.


Assuntos
Proteína BRCA1/genética , Replicação do DNA/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Linhagem Celular , Cisplatino/farmacologia , DNA/genética , DNA/metabolismo , DNA de Cadeia Simples/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , RNA Helicases/genética , Rad51 Recombinase/genética , Proteína de Replicação A/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
14.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298999

RESUMO

The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Cisplatino/uso terapêutico , Glicólise/efeitos dos fármacos , Humanos , Cinurenina/metabolismo , NAD/metabolismo , Oxirredução , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sirtuínas/metabolismo
15.
Life Sci ; 282: 119802, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237314

RESUMO

AIM: To investigate the anti-cancer potential of salicylic acid and cisplatin combination in HeLa cells and the underlying mechanism. MAIN METHODS: Drugs and disease targets were extracted from DrugBank, BATMAN-TCM, STITCH, PharmMapper and Comparative Toxigenomics Database. Cytoscape 3.8.2 was used to merge the protein-protein interaction networks and select core targets. GO and KEGG analysis was done using Metascape and WebGestalt. Effect of salicylic acid and cisplatin alone and in combination on cells viability was studied by MTT assay. The type of interaction between salicylic acid and cisplatin was determined by CompuSyn. Apoptosis was evaluated by molecular docking, Rhodamine-123, DAPI, AO/EtBr staining, flow cytometry, qRT-PCR and western blotting. Metastasis was studied using scratch assay and western blotting. UHRF1 transient silencing was performed by siRNA. KEY FINDINGS: Out of 420, 1863 and 1362 respective targets of salicylic acid, cisplatin and cervical cancer, 18 core proteins were enriched in apoptosis and cell migration related pathways. IC50 value of cisplatin was reduced by 14 fold in combination with salicylic acid at IC20 (4 µM). There was loss of mitochondrial membrane potential and downregulation of UHRF1, pAkt, full length PARP and pro-caspase 3 expression. Transient silencing of UHRF1 also induced mitochondrial depolarization and apoptosis. The combination also exhibited anti-metastasis effect as it suppressed migration, upregulated PAX1 and downregulated MMP-2. SIGNIFICANCE: Reduction in cisplatin concentration, enhanced anti-cancer effects and UHRF1 downregulation due to synergistic interaction between salicylic acid and cisplatin underscores the therapeutic importance of the combination to overcome chemo-resistance and side effects of cisplatin.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Ácido Salicílico/farmacologia , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Células HeLa , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico
16.
J Cancer Res Clin Oncol ; 147(9): 2591-2607, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34213662

RESUMO

PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Leucemia/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose , Proliferação de Células , Cisplatino/farmacologia , Humanos , Leucemia/metabolismo , Leucemia/patologia , Ligantes , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Células Tumorais Cultivadas
17.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328193

RESUMO

Lung cancer is one of the most prevalent cancers in China, and its incidence and morbidity remain high due to various independent factors. Lung adenocarcinoma (ADC) is the most common type of non­small cell lung carcinoma. Circular RNA plasmacytoma variant translocation 1 (circ­PVT1) plays an oncogenic role in various types of cancer, but the specific role of circ­PVT1 in lung ADC has not yet been reported. In the present study, circ­PVT1 was knocked down in A549 cells and the cell viability, proliferation, migration and invasion were measured via MTT, colony formation, wound healing and Transwell assays, respectively. Then, the cell viability of A549 cells with circ­PVT1­knockdown or ­overexpression was detected after exposure to cisplatin (DDP). After confirming the associations among circ­PVT1, microRNA (miR)­429 and forkhead box k1 (FOXK1) using various tools and assays, the cellular functions of A549 cells treated with combined short hairpin (sh)RNA­circ­PVT1 and miR­429 inhibitor/pcDNA3.1­FOXK1 were tested again. The expression of circ­PVT1 was found to be increased in lung ADC cells, and shRNA­circ­PVT1 led to decreased cell viability, proliferation, migration and invasion. The expression of circ­PVT1 was higher in A549/DDP cells than that in A549 cells, and the activity of caspase­3 was also activated by DDP in A549/DDP cells transfected with shRNA­circ­PVT1, whereas it was inactivated by DDP in A549 cells transfected with circ­PVT1 overexpression plasmid. Furthermore, the decreased cell viability, proliferation, invasion and migration induced by shRNA­circ­PVT1 could be abated by transfection with miR­429 inhibitor and pcDNA3.1­FOXK1. In conclusion, interference of circ­PVT1 inhibits the progression of lung ADC and enhances its sensitivity to DDP via miR­429/FOXK1, which may provide a theoretical basis for the use of novel targets in the treatment of lung ADC.


Assuntos
Adenocarcinoma de Pulmão/genética , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Forkhead/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
18.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299320

RESUMO

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Neovascularização Patológica/induzido quimicamente , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Fluoruracila/metabolismo , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Talidomida/farmacologia , Timidina Fosforilase/genética , Regulação para Cima/efeitos dos fármacos
19.
Anticancer Res ; 41(7): 3481-3487, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230143

RESUMO

BACKGROUND/AIM: Metformin is an antidiabetic drug that has been reported to have antitumor activity in many cancer types. This study investigated the molecular mechanisms underlying the antitumor effect of metformin. MATERIALS AND METHODS: We investigated the molecular mechanism of the antitumor effect of metformin alone and in combination with AKT serine/threonine kinase (AKT) inhibition via cell viability and western blot analyses. RESULTS: Notably, metformin increased the phosphorylation of AKT at serine 473 using protein array screening. Metformin-induced AKT activation was markedly suppressed by siRNA targeting activating transcription factor 4 (ATF4) but not AMP-activated protein kinase α. These results indicate that AKT activation by metformin was induced in an ATF4-dependent and AMPKα-independent manner. Treatment using metformin combined with MK-2206, an AKT inhibitor, or a siRNA for AKT markedly reduced the viability of cells compared with those cells treated with these agents alone. In addition, MK-2206 increased cell sensitivity to the combination of metformin with ionizing radiation or cisplatin. CONCLUSION: Inhibition of AKT can enhance the antitumor effect of metformin and would be a promising strategy to sensitize non-small-cell lung cancer to a combination of metformin with radiation or cisplatin.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Metformina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Neoplasias Pulmonares/metabolismo
20.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204834

RESUMO

In head and neck cancers, the effectiveness of cisplatin (CisPt) treatment is limited by its toxicity, especially when higher doses are necessary, and the possible occurrence of cisplatin resistance. This study evaluated the effects of resveratrol (RSV) on the expression of different genes involved in the response of human tumor cells (FaDu, PE/CA-PJ49) to cisplatin therapy. Our results revealed that RSV induced apoptosis amplification in both FaDu and PE/CA-PJ49 cells and modulated the expression of specific genes differently than in normal HaCaT cells. In FaDu cells, combined CisPt + RSV treatment induced an increase in apoptosis, which was associated with an increase in c-MYC and TP53 and a decrease in BCL-2 expression. While CisPt + RSV treatment induced apoptosis in PE/CA-PJ49 cells by inhibition of BCL-2 associated with high levels of MDM-2 and subsequently led to inhibition of TP53 gene expression. Decreased c-MYC expression in PE/CA-PJ49 treated with CisPt + RSV was accompanied by cell cycle blockage in G0/G1 phase. In conclusion, RSV influences tumor cell response to CisPt by inducing apoptosis and modulating gene expression. In addition, in normal HaCaT cells, RSV was able to reduce the harmful effects of CisPt.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Resveratrol/farmacologia , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Concentração Inibidora 50
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