RESUMEN
We present a case of an adenoid cystic carcinoma (ACC) located in the upper trachea, which resulted in significant airway blockage, that was unsuitable for surgical removal due to concerns about functional impairment. Instead, endotracheal enucleation via rigid bronchoscopy was performed initially, followed by the injection of a novel tumor ablation agent known as para-toluenesulfonamide (PTS). We detail the dosing regimen, effectiveness evaluation, and post-treatment follow-up. The study highlights the potential of PTS injection as a viable alternative treatment option for patients with ACC who cannot undergo surgical resection and feasibility of lipiodol to monitor treatment effect. This research adds to the existing knowledge on ACC treatment and provides new therapeutic possibilities for patients with tracheal ACC.
Asunto(s)
Carcinoma Adenoide Quístico , Neoplasias de la Tráquea , Humanos , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/cirugía , Carcinoma Adenoide Quístico/patología , Neoplasias de la Tráquea/tratamiento farmacológico , Neoplasias de la Tráquea/cirugía , Femenino , Compuestos de Tosilo/uso terapéutico , Compuestos de Tosilo/administración & dosificación , Persona de Mediana Edad , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Masculino , Broncoscopía/métodos , Bencenosulfonamidas , Tolueno/análogos & derivadosRESUMEN
Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl2), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl2-induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer.
Asunto(s)
Neoplasias de la Mama , Anhidrasas Carbónicas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Femenino , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Anhidrasas Carbónicas/metabolismo , Anhidrasas Carbónicas/farmacología , Supervivencia Celular , Factor A de Crecimiento Endotelial Vascular/metabolismo , Antígenos de Neoplasias/metabolismo , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Hipoxia de la Célula , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Línea Celular Tumoral , Neoplasias de la Mama/patologíaRESUMEN
The pharmacological pathway of para-toluenesulfonamide (PTS) restricts the kinase activity of the mammalian target of rapamycin, potentially leading to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical effect on tumorigenesis. We aimed to examine the antitumor effect of PTS or PTS combined with cisplatin on canine melanoma implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. The mice were randomly divided into four groups: control, cisplatin, PTS, and PTS combined with cisplatin. Mice treated with PTS or PTS combined with cisplatin had retarded tumor growth and increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase phosphorylation, decreased inflammatory cytokine levels, reduced inflammation-related factors, enhanced anti-inflammation-related factors, and inhibition of metastasis-related factors. Mice treated with PTS combined with cisplatin exhibited significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with those treated with cisplatin or PTS alone. PTS or PTS combined with cisplatin could retard canine melanoma growth and inhibit tumorigenesis. PTS and cisplatin were found to have an obvious synergistic tumor-inhibiting effect on canine melanoma. PTS alone and PTS combined with cisplatin may be antitumor agents for canine melanoma treatment.
RESUMEN
Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action.
Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Membrana Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Autofagia/fisiología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Colesterol/metabolismo , Gefitinib/administración & dosificación , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Tolueno/administración & dosificación , Tolueno/análogos & derivados , Tolueno/farmacologíaRESUMEN
Castration-resistant prostate cancer (CRPC) cells can resist many cellular stresses to ensure survival. There is an unmet medical need to fight against the multiple adaptive mechanisms in cells to achieve optimal treatment in patients. Para-toluenesulfonamide (PTS) is a small molecule that inhibited cell proliferation of PC-3 and DU-145, two CRPC cell lines, through p21- and p27-independent G1 arrest of cell cycle in which cyclin D1 was down-regulated and Rb phosphorylation was inhibited. PTS also induced a significant loss of mitochondrial membrane potential that was attributed to up-regulation of both Bak and PUMA, two pro-apoptotic Bcl-2 family members, leading to apoptosis. PTS inhibited the phosphorylation of m-TOR, 4E-BP1, and p70S6K in both cell lines. Overexpression of constitutively active Akt rescued the inhibition of mTOR/p70S6K signaling in PC-3 cells indicating an Akt-dependent pathway. In contrast, Akt-independent effect was observed in DU-145 cells. Lipid rafts serve as functional platforms for multiple cellular signaling and trafficking processes. Both cell lines expressed raft-associated Akt, mTOR, and p70S6K. PTS induced decreases of expressions in both raft-associated total and phosphorylated forms of these kinases. PTS-induced inhibitory effects were rescued by supplement of cholesterol, an essential constituent in lipid raft, indicating a key role of cholesterol contents. Moreover, the tumor xenograft model showed that PTS inhibited tumor growth with a T/C (treatment/control) of 0.44 and a 56% inhibition of growth rate indicating the in vivo efficacy. In conclusion, the data suggest that PTS is an effective anti-tumor agent with in vitro and in vivo efficacies through inhibition of both Akt-dependent and -independent mTOR/p70S6K pathways. Moreover, disturbance of lipid raft and cholesterol contents may at least partly explain PTS-mediated anti-tumor mechanism.
RESUMEN
Pulmonary adenoid cystic carcinoma (ACC) is a rare type of non-small cell lung carcinoma that may develop life-threatening severe malignant airway obstruction (SMAO). Currently, limited therapeutic approaches exist for ACC-SMAO. We investigated the efficacy and safety of para-toluenesulfonamide (PTS) intratumoral injection for ACC-SMAO. In this phase III, multicenter, non-randomized, single-arm, open-label trial, we recruited eight hospitalized patients with ACC-SMAO between October 2009 and January 2011. Within the first year, patients received PTS injection for 2-3 sessions weekly, with 2 weeks as a single course. Pre- and post-treatment assessments, including vital sign assessment, dyspnea index, chest computed tomography (CT), were performed shortly before PTS injection and at day 30 post-treatment. We extended the observation to 5 years to determine overall survival. The primary endpoint was the CT-assessed airway objective response rate (ORR) at day 30. The key secondary endpoint was the overall survival (OS) at 5 years post-treatment. At baseline, mean airway tumor cross-sectional area was 153.3 mm2 (n=8), and the mean airway obstruction rate was 86.1%. The airway ORR reached 100% (33.3% complete remission and 66.7% partial remission). PTS treatment reduced the airway tumor size from 158.2 to 22.7 mm2 and the average airway obstruction rate decreased from 83.1% to 14.4% (n=6). The 5-year overall survival rate was 50.0%. Median survival duration was 4.98 years (range, 1.39-5.00 years). Four patients (50.0%) had stable disease. Compared with baseline dyspnea index, the transitional dyspnea index increased significantly at 30 days after treatment (mean difference: 5.40; 95% CI, 0.31-10.49; P<0.05). Adverse events were reported in 75% of patients (n=6), of whom 33.3% (n=2) and 66.7% (n=4) were rated as mild and moderate, respectively. No SAE was reported. In conclusion, PTS could rapidly debulk ACC-SMAO, resulting in considerable improvement of five-year survival rate.
RESUMEN
BACKGROUND: Severe malignant airway obstruction (SMAO) is a life-threatening form of non-small cell lung carcinoma (NSCLC). OBJECTIVES: To determine the efficacy and safety of para-toluenesulfonamide (PTS) intratumoral injection in NSCLC-SMAO. METHODS: Ninety patients with NSCLC-SAO received repeated courses of PTS intratumoral injection until tumor sizes had reduced by 50% or greater. Primary endpoint was objective alleviation rate, assessed by chest computed tomography (CT) and bronchoscopy, at day 7 and 30 following final dosing. Secondary endpoints included airway obstruction, spirometry, quality-of-life and survival time. RESULTS: In full-analysis set (N=88), using RECIST criteria, PTS treatment resulted in a significant objective alleviation rate [chest CT: 59.1% (95%CI: 48.1%-69.5%), bronchoscopy: 48.9% (95%CI: 38.1%-59.8%) at day 7; chest CT: 43.2% (95%CI: 32.7%-54.2%), bronchoscopy: 29.6% (95%CI: 20.3%-40.2%) at day 30]. There was a remarkable increase in FVC (mean difference: 0.35 liters, 95%CI: 0.16-0.53 liters), FEV1 (mean difference: 0.27 liters, 95%CI: 0.07-0.48 liters), Baseline Dyspnea Index (mean difference: 64.8%, 95%CI: 53.9-74.7%) and Functional Assessment of Cancer Therapy-Lung Cancer Subscale (mean difference: 6·9, 95%CI: 3.8-9.9) at day 7 post-treatment. We noted significantly reduced prevalence of atelectasis (by 42.9%) and Eastern Cooperative Oncology Group physical performance scale (mean difference: 7.2, 95%CI: 3.9-10.5). Median survival time was 394 days in full-analysis set and 460 days in per-protocol set. Adverse events were reported in 64.0% of subjects. Seven severe adverse events (7.9%) were reported, of which three led to death (drug-related in one case). CONCLUSION: PTS intratumoral injection is effective and well tolerated for palliative therapy of NSCLC-SMAO.
Asunto(s)
Obstrucción de las Vías Aéreas/complicaciones , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Tolueno/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Obstrucción de las Vías Aéreas/diagnóstico , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Inyecciones Intralesiones , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sulfonamidas/efectos adversos , Análisis de Supervivencia , Tolueno/administración & dosificación , Tolueno/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Conventional chemotherapy and radiation therapy against non-small cell lung cancer (NSCLC) are relatively insensitive and unsatisfactory. Para-toluenesulfonamide (PTS), a unique antitumor drug for local intratumoral injection, shows an efficacy of severely suppressing solid tumor growth with mild side effects in clinical trials. The aim of this study was to investigate the effect of PTS on lung cancer H460 cells in vivo in nude mice and its underlying mechanisms in vitro. METHODS: A lung cancer model for in vivo experiment was established in BALB/c nude mice using H460 cells to examine the effect of local injection of PTS on tumor suppression. We also assessed the injury to the normal tissue by subcutaneous injection of PTS. In vitro, PTS was diluted into different doses for study on its antitumor mechanisms. We evaluated the necrotic effect of PTS on H460 cells by PI and Hoechst 33342 staining. Cell viability and membrane permeability were also determined by using CCK-8 and LDH assays respectively. All these tests were conducted in comparison with traditional local injection of anhydrous ethanol. RESULTS: PTS was shown to significantly inhibit the growth of H460 tumor xenografts in nude mice by inducing necrosis of the tumor histologically. Its effect on tumor growth was significantly stronger than that of anhydrous ethanol. By contrast, the injured normal tissue by PTS injection was less than that by ethanol. In vitro, PTS still demonstrated excellent necrotizing effect on H460 cells when diluted to a lower concentration. Detailed analysis of PTS on H460 cells indicated that PTS had a better effect on attenuating the cell viability and increasing the cell membrane permeability than ethanol at the same level. CONCLUSIONS: PTS exhibits excellent inhibition effect on the growth of lung cancer by necrotizing tumor in vivo and in vitro, reducing tumor cell viability and augmenting the membrane permeability in vitro, with only mild injury to normal tissue. The antitumor effect of PTS on lung cancer in vivo and in vitro is stronger than that of ethanol.
RESUMEN
Hepatocellular carcinoma (HCC) is difficult to eradicate due to its resilient nature. Portal vein is often involved in tumors of large size, which exclude the patient from surgical resection and local ablative therapy, such as percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) because they were considered neither effective nor safe. Currently, there is almost no effective treatment for HCC of such condition. As a unique antitumor agent in form of lipophilic fluid for local injection, para-toluenesulfonamide (PTS) produces mild side effects while necrotizing the tumor tissues quickly and efficiently. Being largely different from both PEI and RFA therapies, PTS can disseminate itself in tumors more easily than other caustic agents, such as alcohol. So PTS may offer additional benefit to HCCs with vascular involvement. We herein describe a 70-year-old HCC patient who was treated with the combination of PTS injection and transcatheter arterial chemoembolization, resulting in a significantly improved clinical prognosis.