RESUMO
Photothermal therapy (PTT) holds great promise as a cancer treatment modality by generating localized heat at the tumor site. Among various photothermal agents, gallium-based liquid metal (LM) has been widely used as a new photothermal-inducible metallic compound due to its structural transformability. To overcome limitations of random aggregation and dissipation of administrated LM particles into a human body, we developed LM-containing injectable composite hydrogel platforms capable of achieving spatiotemporal PTT and chemotherapy. Eutectic gallium-indium LM particles were first stabilized with 1,2-Distearoyl-snglycero-3-phosphoethanolamine (DSPE) lipids. They were then incorporated into an interpenetrating hydrogel network composed of thiolated gelatin conjugated with 6-mercaptopurine (MP) chemodrug and poly(ethylene glycol)-diacrylate. The resulted composite hydrogel exhibited sufficient capability to induce MDA-MB-231 breast cancer cell death through a multi-step mechanism: (1) hyperthermic cancer cell death due to temperature elevation by near-infrared laser irradiation via LM particles, (2) leakage of glutathione (GSH) and cleavage of disulfide bonds due to destruction of cancer cells. As a consequence, additional chemotherapy was facilitated by GSH, leading to accelerated release of MP within the tumor microenvironment. The effectiveness of our composite hydrogel system was evaluated both in vitro and in vivo, demonstrating significant tumor suppression and killing. These results demonstrate the potential of this injectable composite hydrogel for spatiotemporal cancer treatment. In conclusion, integration of PTT and chemotherapy within our hydrogel platform offers enhanced therapeutic efficacy, suggesting promising prospects for future clinical applications. STATEMENT OF SIGNIFICANCE: Our research pioneers a breakthrough in cancer treatments by developing an injectable hydrogel platform incorporating liquid metal (LM) particle-mediated photothermal therapy and 6-mercaptopurine (MP)-based chemotherapy. The combination of gallium-based LM and MP achieves synergistic anticancer effects, and our injectable composite hydrogel acts as a localized reservoir for specific delivery of both therapeutic agents. This platform induces a multi-step anticancer mechanism, combining NIR-mediated hyperthermic tumor death and drug release triggered by released glutathione from damaged cancer populations. The synergistic efficacy validated in vitro and in vivo studies highlights significant tumor suppression. This injectable composite hydrogel with synergistic therapeutic efficacy holds immense promise for biomaterial-mediated spatiotemporal treatment of solid tumors, offering a potent targeted therapy for triple negative breast cancers.
Assuntos
Neoplasias da Mama , Gálio , Hidrogéis , Hidrogéis/química , Gálio/química , Gálio/farmacologia , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Animais , Linhagem Celular Tumoral , Injeções , Fototerapia , Camundongos Nus , Camundongos , Terapia Fototérmica , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND/AIM: Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC. MATERIALS AND METHODS: Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments. RESULTS: Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid. CONCLUSION: These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.
Assuntos
Neoplasias Ovarianas , Oxazóis , Piperazinas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/metabolismoRESUMO
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Animais , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Recidiva Local de Neoplasia , Paclitaxel/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Transportadores de Cassetes de Ligação de ATP , Proteínas de Neoplasias/metabolismo , Antígenos CD/uso terapêutico , Proteínas Ligadas por GPI/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
NANOG, a stemness-associated transcription factor, is highly expressed in many cancers and plays a critical role in regulating tumorigenicity. Transformation/transcription domain-associated protein (TRRAP) has been reported to stimulate the tumorigenic potential of cancer cells and induce the gene transcription of NANOG. This study aimed to investigate the role of the TRRAP-NANOG signaling pathway in the tumorigenicity of cancer stem cells. We found that TRRAP overexpression specifically increases NANOG protein stability by interfering with NANOG ubiquitination mediated by FBXW8, an E3 ubiquitin ligase. Mapping of NANOG-binding sites using deletion mutants of TRRAP revealed that a domain of TRRAP (amino acids 1898-2400) is responsible for binding to NANOG and that the overexpression of this TRRAP domain abrogated the FBXW8-mediated ubiquitination of NANOG. TRRAP knockdown decreased the expression of CD44, a cancer stem cell marker, and increased the expression of P53, a tumor suppressor gene, in HCT-15 colon cancer cells. TRRAP depletion attenuated spheroid-forming ability and cisplatin resistance in HCT-15 cells, which could be rescued by NANOG overexpression. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model, which could be reversed by NANOG overexpression. Together, these results suggest that TRRAP plays a pivotal role in the regulation of the tumorigenic potential of colon cancer cells by modulating NANOG protein stability.
Assuntos
Neoplasias do Colo , Animais , Humanos , Camundongos , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/metabolismo , Estabilidade ProteicaRESUMO
Epithelial ovarian cancer is a gynecological cancer with the highest mortality rate, and it exhibits resistance to conventional drugs. Gold nanospheres have gained increasing attention over the years as photothermal therapeutic nanoparticles, owing to their excellent biocompatibility, chemical stability, and ease of synthesis; however, their practical application has been hampered by their low colloidal stability and photothermal effects. In the present study, we developed a yolk-shell-structured silica nanocapsule encapsulating aggregated gold nanospheres (aAuYSs) and examined the photothermal effects of aAuYSs on cell death in drug-resistant ovarian cancers both in vitro and in vivo. The aAuYSs were synthesized using stepwise silica seed synthesis, surface amino functionalization, gold nanosphere decoration, mesoporous organosilica coating, and selective etching of the silica template. Gold nanospheres were agglomerated in the confined silica interior of aAuYSs, resulting in the red-shifting of absorbance and enhancement of the photothermal effect under 808 nm laser irradiation. The efficiency of photothermal therapy was first evaluated by inducing aAuYS-mediated cell death in A2780 ovarian cancer cells, which were cultured in a two-dimensional culture and a three-dimensional spheroid culture. We observed that photothermal therapy using aAuYSs together with doxorubicin treatment synergistically induced the cell death of doxorubicin-resistant A2780 cancer cells in vitro. Furthermore, this type of combinatorial treatment with photothermal therapy and doxorubicin synergistically inhibited the in vivo tumor growth of doxorubicin-resistant A2780 cancer cells in a xenograft transplantation model. These results suggest that photothermal therapy using aAuYSs is highly effective in the treatment of drug-resistant cancers.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ouro/farmacologia , Nanopartículas Metálicas/química , Neoplasias Ovarianas/tratamento farmacológico , Terapia Fototérmica , Animais , Antibióticos Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ouro/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3ß inactivation by augmenting AKT-dependent phosphorylation of GSK3ß at Ser9, followed by increasing ß-catenin level via reducing the GSK3ß-mediated phosphorylation of ß-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide-3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of ß-catenin protein via the AKT-GSK3ß-dependent pathways.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Humanos , Transdução de SinaisRESUMO
Cancer stem cells (CSCs) or tumor-initiating cells are thought to play critical roles in tumorigenesis, metastasis, drug resistance, and tumor recurrence. For the diagnosis and targeted therapy of CSCs, the molecular identity of biomarkers or therapeutic targets for CSCs needs to be clarified. In this study, we identified CD166 as a novel marker expressed in the sphereforming CSC population of A2780 epithelial ovarian cancer cells and primary ovarian cancer cells. The CD166+ cells isolated from A2780 cells and primary ovarian cancer cells highly expressed CSC markers, including ALDH1a1, OCT4, and SOX2, and ABC transporters, which are implicated in the drug resistance of CSCs. The CD166+ cells exhibited enhanced CSC-like properties, such as increased sphere-forming ability, cell migration and adhesion abilities, resistance to conventional anticancer drugs, and high tumorigenic potential in a xenograft mouse model. Knockdown of CD166 expression in the sphereforming ovarian CSCs abrogated their CSC-like properties. Moreover, silencing of CD166 expression in the sphere-forming CSCs suppressed the phosphorylation of focal adhesion kinase, paxillin, and SRC. These results suggest that CD166 plays a key role in the regulation of CSC-like properties and focal adhesion kinase signaling in ovarian cancer. [BMB Reports 2020; 53(12): 622-627].