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The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells. ATR inhibitors have been used in clinical trials in combination with radiation or chemotherapeutics; however, their effects against bladder cancer remain unclear. Here, the efficacy of combining gemcitabine with the novel ATR inhibitor AZD6738 was investigated in vitro in three bladder cancer cell lines (J82, T24, and UM-UC-3 cells). The effects of gemcitabine and AZD6738 on cell viability, clonogenicity, cell cycle, and apoptosis were examined. The combined use of gemcitabine and AZD6738 inhibited the viability and colony formation of bladder cancer cells compared to either treatment alone. Gemcitabine (5 nM) and AZD6738 (1 µM) inhibited cell cycle progression, causing cell accumulation in the S phase. Moreover, combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin V-positive cells, indicating apoptosis induction. Mechanistic investigations showed that AZD6738 treatment inhibited the repair of gemcitabine-induced double-strand breaks by interfering with CHK1. Combining AZD6738 with gemcitabine could therefore be useful for bladder cancer therapy.
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Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas Mutadas de Ataxia Telangiectasia , Quinase 1 do Ponto de Checagem , Desoxicitidina , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Sulfóxidos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , GencitabinaRESUMO
BACKGROUND/AIM: Simultaneous inhibition of histone deacetylase and proteasomes induces endoplasmic reticulum (ER) stress efficiently. RTS-V5 is the first dual histone deacetylase-proteasome inhibitor, and we anticipated that combining it with the cytochrome P450 family 3 subfamily A member 4 inhibitor ritonavir would enhance its activity in bladder cancer cells. MATERIALS AND METHODS: Using bladder cancer cells (human T-24, J-82, murine MBT-2), we evaluated the ability and mechanism by which the combination of RTS-V5 and ritonavir induced ER stress and killed cancer cells. RESULTS: The combination of RTS-V5 and ritonavir triggered robust apoptosis and inhibited bladder cancer growth effectively in vitro and in vivo. It caused ubiquitinated protein accumulation and induced ER stress synergistically. The combination inhibited the mammalian target of rapamycin pathway by increasing the expression of AMP-activated protein kinase. We also found that the combination caused histone and tubulin hyperacetylation. CONCLUSION: Ritonavir enhances the ability of RTS-V5 to cause ER stress in bladder cancer cells.
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Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteassoma/farmacologia , Ritonavir/farmacologia , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Histonas/metabolismo , Humanos , Camundongos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination's action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination's ability to induce apoptosis. We also found that the combination increased the expression of peroxisome proliferator-activated receptor (PPAR) γ, leading to reactive oxygen species production. Furthermore, the combination induced endoplasmic reticulum (ER) stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination's action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression.
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BACKGROUND/AIM: Activation of the ubiquitin-proteasome system (UPS) has been shown to be associated with drug resistance in cancer. Using bladder cancer cells, we investigated the association between UPS activation and cisplatin resistance and also the efficacy of UPS-targeting drugs. MATERIALS AND METHODS: We established cisplatin-resistant bladder cancer cells (J82-cisR, T24-cisR) and examined the activation status of the UPS and the efficacy of MLN7243, oprozomib, ixazomib, and RTS-V5. RESULTS: The UPS in cisplatin-resistant bladder cancer cells was activated compared to that in their parental controls. All the UPS-targeting drugs induced apoptosis and inhibited growth more effectively in the cisplatin-resistant bladder cancer cells than they did in the parental controls. Furthermore, these UPS-targeting drugs induced endoplasmic reticulum stress by causing unfolded protein accumulation at lower concentrations in the cisplatin-resistant bladder cancer cells. CONCLUSION: Targeting the UPS could be an effective strategy for treating cisplatin-resistant bladder cancer.
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Antineoplásicos/farmacologia , Cisplatino/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Neoplasias da Bexiga Urinária/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , HumanosRESUMO
Checkpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemcitabine with MK-8776, a novel CHK1 inhibitor, in four bladder cancer cell lines. The effects of gemcitabine and MK-8776 on cell viability, clonogenicity, cell cycle, and apoptosis were examined alongside in vivo efficacy using murine xenograft tumor models. Combined treatment inhibited the viability and colony formation of bladder cancer cells compared to either single treatment. Although gemcitabine (10 nM) alone increased the cell number in S-phase, it increased the cell number in sub-G1 phase when combined with MK-8776 (0.5 µM). Combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin-V-positive cells, indicating the induction of apoptosis. In vivo, administration of gemcitabine and MK-8776 was well tolerated and suppressed tumor growth. Mechanistically, the combined treatment elevated γH2A.X and suppressed Rad51 expression. Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Desoxicitidina/análogos & derivados , Pirazóis/farmacologia , Pirimidinas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/metabolismo , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Necrose/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
A 74-year-old male patient with stage D1 prostate cancer with the initial prostate-specific antigen (PSA) level of 5570 ng/mL had received androgen deprivation therapy and the serum PSA level had decreased to 0.23 ng/mL when he developed macroscopic hematuria. MRI and cystoscopy suggested invasive urothelial cancer of the bladder, and transurethral resection was performed. The tumors were pathologically diagnosed as a Gleason score 9 prostate cancer with no PSA expression. Prostate cancer patients who develop novel symptoms should be screened for prostate cancer recurrence even if they have very low PSA levels.
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We report a case of unusually aggressive behavior of a mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney with no sarcomatoid changes. A 43-year-old man was referred to our hospital for a mass on his left kidney. Computed tomography revealed a tumor at the upper pole of the kidney and swollen lymph nodes. Left radical nephrectomy with lymph node dissection was performed and the tumor was diagnosed as MTSCC. Peritoneal dissemination was detected 4 months after the surgery. The patient received systemic treatments, which were not effective. He finally died of the disease 12 months after the surgery.
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Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.
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Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Fluvastatina/farmacologia , Neoplasias Renais/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND/AIM: Induction of endoplasmic reticulum (ER) stress is a novel approach to cancer treatment. This study investigated the ability of the clinically feasible combination of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir to induce ER stress killing urological cancer cells. MATERIALS AND METHODS: Renal cancer cells (769-P, 786-O) and bladder cancer cells (UMUC-3, T-24) were used to investigate the ability of the combination to induce ER stress and its mechanism of action. RESULTS: The combination inhibited the growth of both renal and bladder cancer cells synergistically by inducing ER stress. The combination-induced ER stress increased the expression of AMP-activated protein kinase and suppressed the mammalian target of rapamycin pathway. It also increased the expression of a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor and thereby sensitized the cancer cells to TRAIL. CONCLUSION: The combination of lopinavir and ritonavir acts against urological cancer cells by inducing ER stress synergistically.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Lopinavir/farmacologia , Ritonavir/farmacologia , Neoplasias Urológicas/tratamento farmacológico , Quimioterapia Combinada , Humanos , Células Tumorais Cultivadas , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologiaRESUMO
Panobinostat, a histone deacetylase inhibitor, induces histone acetylation and acts against cancer but attenuates its anticancer activity by activating the mammalian target of rapamycin (mTOR) pathway. AMP-activated protein kinase (AMPK) is a cellular energy sensor that reportedly inhibits the mTOR pathway. The antidiabetic drug metformin is also a potent AMPK activator and we investigated whether it augmented panobinostat's antineoplastic activity in bladder cancer cells (UMUC3, J82, T24 and MBT-2). Metformin enhanced panobinostat-induced apoptosis and the combination inhibited the growth of bladder cancer cells cooperatively in vitro and in vivo. As expected, metformin increased the phosphorylation of AMPK and decreased the panobinostat-caused phosphorylation of S6 ribosomal protein, thus inhibiting the panobinostat-activated mTOR pathway. The AMPK activation was shown to play a pivotal role in the combination's action because the AMPK inhibitor compound C attenuated the combination's anticancer activity. Furthermore, the AMPK activation by metformin enhanced panobinostat-induced histone and non-histone acetylation. This acetylation was especially remarkable in the proteins in the detergent-insoluble fraction, which would be expected if the combination also induced endoplasmic reticulum stress.
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BACKGROUND/AIM: There is no curative treatment for patients with advanced renal cancer. We believed that the combination of the histone deacetylase inhibitor panobinostat and the human immunodeficiency virus protease inhibitor nelfinavir would kill renal cancer cells by inducing endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: Using renal cancer cells (769-P, 786-O, Caki-2), the ability of this combination to induce ER stress and its mechanism of action were investigated. RESULTS: The combination of drugs induced apoptosis and inhibited cancer growth effectively both in vitro and in vivo. Mechanistically, the combination induced ER stress and histone acetylation cooperatively. ER stress induction was shown to play a pivotal role in the anticancer effect of the combination because the protein synthesis inhibitor cycloheximide significantly attenuated combination-induced apoptosis. Nelfinavir was also found to increase the expression of the mammalian target of rapamycin (mTOR) inhibitor AMP-activated protein kinase (AMPK) and inhibited the panobinostat-activated mTOR pathway. CONCLUSION: Panobinostat and nelfinavir inhibit renal cancer growth by inducing ER stress.
Assuntos
Carcinoma de Células Renais/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Neoplasias Renais/patologia , Nelfinavir/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Inibidores da Protease de HIV/farmacologia , Humanos , Neoplasias Renais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Panobinostat , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIM: In the present study, the antineoplastic activity and mechanism of action of phenoxodiol, a novel isoflavone analog, was investigated in renal cancer cells. MATERIALS AND METHODS: A panel of renal cancer cells (769-P, 786-O, Caki-2) was treated with phenoxodiol in vitro, and the efficacy of treatment was evaluated. RESULTS: MTS assay results showed that phenoxodiol decreased renal cancer viability in a dose-dependent manner. In addition, it inhibited colony formation significantly and perturbed the cell cycle. Treatment with phenoxodiol increased the number of annexin-V-positive cells as well as the expression of cleaved poly ADP ribose polymerase, demonstrating that phenoxodiol induced apoptosis in renal cancer cells. Phenoxodiol also inhibited Akt pathway via dephosphorylation of Akt. CONCLUSION: Phenoxodiol inhibited Akt pathway and induced apoptosis of renal cancer cells. The present study provides a theoretical basis for future development of a novel therapy effective against renal cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Neoplasias Renais/patologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais CultivadasRESUMO
Bosniak category III renal cystic masses are often treated with surgical resection because of high risk of malignancy. Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor used to treat ALK gene-rearranged non-small cell lung cancer and reported to be associated with complex renal cyst formation. We herein report a case of Bosniak category III renal cysts occurred in a crizotinib-treated ALK gene-rearranged non-small cell lung cancer patients. The cysts regressed spontaneously after cessation of crizotinib and we could thus avoid unnecessary surgical resection.
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BACKGROUND/AIM: Induction of endoplasmic reticulum (ER) stress is a novel strategy for cancer treatment. The human immunodeficiency virus protease inhibitor nelfinavir was recently shown to induce ER stress, but its anti-neoplastic activity has never been investigated in renal cancer, as far as we are aware. MATERIALS AND METHODS: Using renal cancer cells (769-P, 786-O, Caki-2), the ability of nelfinavir to induce ER stress and sensitize them to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was tested. RESULTS: Nelfinavir caused apoptosis and inhibited renal cancer growth in a dose-dependent fashion. It also suppressed colony formation significantly. Nelfinavir induced ER stress and increased the expression of TRAIL death receptor (DR) 4 and DR5, sensitizing the cancer cells to TRAIL. This sensitization was blocked by human recombinant DR4/Fc and DR5/Fc chimeric protein, confirming that the sensitization was due to increased expression of both DR4 and DR5. CONCLUSION: Nelfinavir induces ER stress in renal cancer cells and sensitizes them to TRAIL.
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Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Nelfinavir/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismoRESUMO
Pazopanib is an orally bioavailable tyrosine kinase inhibitor anticancer drug approved worldwide for the treatment of metastatic renal cell carcinoma and advanced soft tissue sarcoma. Here we report the case of a patient whose recurrent retroperitoneal soft tissue sarcoma showed a drastic reduction immediately after pazopanib administration accompanied by severe liver dysfunction. His liver function was restored conservatively by giving him hepatoprotectors and having him stop taking pazopanib. The recurrent tumor disappeared but by 4 months later had regrown.
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BACKGROUND/AIM: To investigate the efficacy against renal cancer cells of combining the HIV protease inhibitor ritonavir with the novel proteasome inhibitor delanzomib. MATERIALS AND METHODS: Renal cancer cell lines 769-P, 786-O, Caki-2 and Renca were treated with ritonavir and delanzomib in vitro and in vivo, and the efficacy of combination was evaluated. RESULTS: The combination of ritonavir and delanzomib synergistically inhibited renal cancer growth and suppressed colony formation. It induced robust apoptosis evidenced by increased cell population in the sub-G1 fraction and increased number of annexin-V-positive cells. A 13-day treatment with the combination was well tolerated in the mouse model and inhibited tumor growth significantly. Mechanistically, the combination synergistically induced endoplasmic reticulum stress and inhibited the mammalian target of rapamycin (mTOR) pathway. CONCLUSION: The effectiveness of combination of ritonavir and delanzomib appears to be due to the induction of ER stress and inhibition of the mTOR pathway.
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Ácidos Borônicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ritonavir/farmacologia , Treonina/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Borônicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Sinergismo Farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/farmacologia , Ritonavir/administração & dosagem , Treonina/administração & dosagem , Treonina/farmacologiaRESUMO
The human immunodeficiency virus (HIV) protease inhibitor nelfinavir acts against malignancies by inducing endoplasmic reticulum (ER) stress. The HIV protease inhibitor ritonavir, on the other hand, not only induces ER stress but also inhibits P-glycoprotein's pump activity and thereby enhances the effects of its substrate drugs. We therefore postulated that ritonavir in combination with nelfinavir would kill bladder cancer cells effectively by inducing ER stress cooperatively and also enhancing nelfinavir's effect. Nelfinavir was shown to be a P-glycoprotein substrate, and the combination of nelfinavir and ritonavir inhibited bladder cancer cell growth synergistically. It also suppressed colony formation significantly. The combination significantly increased the number of cells in the sub-G1 fraction and also the number of annexin V+ cells, confirming robust apoptosis induction. The combination induced ER stress synergistically, as evidenced by the increased expression of glucose-regulated protein 78, ER-resident protein 44, and endoplasmic oxidoreductin-1-like protein. It also increased the expression of the mammalian target of rapamycin (mTOR) inhibitor AMP-activated protein kinase and caused dephosphorylation of S6 ribosomal protein, demonstrating that the combination also inhibited the mTOR pathway. We also found that the combination enhanced histone acetylation synergistically by decreasing the expression of HDACs 1, 3, and 6.
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Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nelfinavir/farmacologia , Ritonavir/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Acetilação/efeitos dos fármacos , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Histonas/metabolismo , Humanos , Nelfinavir/metabolismo , Ritonavir/metabolismoRESUMO
OBJECTIVE: To compare the clinical courses of patients with pelvic fracture urethral injury (PFUI) according to initial management strategy. METHODS: We reviewed the clinical courses of 63 patients with PFUI who were initially treated elsewhere and underwent delayed anastomotic urethroplasty by a single surgeon between 2008 and 2015. Patients were grouped according to their initial treatment: by suprapubic tube placement alone (49 patients, SPT group) or primary realignment (14 patients, PR group). Time to urethroplasty was defined as the period between injury and delayed urethroplasty. Clinical data regarding the status of urethral stenosis, urethroplasty procedure, and treatment outcome were analyzed. RESULTS: The mean time to urethroplasty in the PR group was about 3 times than that in the SPT group (133 months vs 47 months, P = .035). Fifty percent of the PR group (7 of 14) had a history of repeated urethrotomy or dilation before referral, a percentage significantly higher than that of the SPT group (20.4%, 10 of 49, P = .027). The percentage of patients having a false passage and iatrogenic scar was significantly higher in the PR group (42.9% vs 16.3%, P = .035), but there was no significant between-group difference in urethral stenosis length, operative time, operative blood loss, or the percentage of patients requiring inferior pubectomy or urethral rerouting. CONCLUSION: PR does not facilitate delayed urethroplasty, and patients who undergo PR are at high risk of having a more complicated stenosis and longer time to urethroplasty, presumably because of repeated transurethral procedures.
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Fraturas Ósseas/complicações , Ossos Pélvicos/lesões , Procedimentos de Cirurgia Plástica/métodos , Uretra/lesões , Estreitamento Uretral/cirurgia , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Adulto , Anastomose Cirúrgica , Cistoscopia , Progressão da Doença , Seguimentos , Fraturas Ósseas/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Técnicas de Sutura , Fatores de Tempo , Índices de Gravidade do Trauma , Resultado do Tratamento , Uretra/diagnóstico por imagem , Uretra/cirurgia , Estreitamento Uretral/diagnóstico , Estreitamento Uretral/etiologiaRESUMO
There is no curative treatment for advanced bladder cancer. Causing ubiquitinated protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock protein 90 and increase the amount of unfolded proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded proteins and thereby causing ubiquitinated proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the sub-G1 fraction significantly. Mechanistically, the combination caused ubiquitinated protein accumulation and endoplasmic reticulum stress. The combination-induced apoptosis was markedly attenuated by the protein synthesis inhibitor cycloheximide, suggesting that the accumulation of ubiquitinated proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel ubiquitinated-protein-accumulation-based therapies effective against bladder cancer.
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Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Glicina/análogos & derivados , Ritonavir/farmacologia , Proteínas Ubiquitinadas/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicina/farmacologia , Humanos , Inibidores de Proteassoma/farmacologia , Ubiquitinação/efeitos dos fármacosRESUMO
The histone deacetylase (HDAC) inhibitor belinostat increases the amount of unfolded proteins in cells by promoting the acetylation of heat shock protein 90 (HSP90), thereby disrupting its chaperone function. The human immunodeficiency virus protease inhibitor ritonavir, on the other hand, not only increases unfolded proteins by suppressing HSP90 but also acts as a proteasome inhibitor. We thought that belinostat and ritonavir together would induce endoplasmic reticulum (ER) stress and kill renal cancer cells effectively. The combination of belinostat and ritonavir induced drastic apoptosis and inhibited the growth of renal cancer cells synergistically. Mechanistically, the combination caused ER stress (evidenced by the increased expression of the ER stress markers) and also enhanced histone acetylation by decreasing the expression of HDACs. To our knowledge, this is the first study that showed a beneficial combined effect of belinostat and ritonavir in renal cancer cells, providing a framework for testing the combination in renal cancer patients.