Para-toluenesulfonamide Research Articles

Targeting hepatocellular carcinoma growth and metabolism: A synergistic approach with para-toluenesulfonamide and radiofrequency ablation

Background and aimsHepatocellular carcinoma (HCC) is one of the most prevalent and lethal forms of cancer, posing challenges to standard treatment methods. Radiofrequency ablation (RFA) has emerged as a valuable technique for the local control of advanced HCC, especially in cases unsuitable for surgical resection. Para-toluenesulfonamide (PTS) has demonstrated antitumor properties in various cancers, yet its efficacy against HCC remains underexplored. The present study aims to investigate the therapeutic potential of PTS in HCC and examine potential synergistic effects with RFA. MethodsPTS was injected directly into subcutaneous tumor tissues and its effects on cell survival, gene expression, and metabolic activity in HCC cells were evaluated. The effect of PTS and RFA in combination on HCC growth was examined using a nude mouse model of subcutaneous HCC. Data were visualized using heat maps. ResultsPTS inhibited the survival of HCC cells in a dose-dependent manner, modulating the expression of key genes related to cell survival, apoptosis, epithelial–mesenchymal transition, and proliferation. The combination of PTS and RFA markedly enhanced the inhibition of HCC tumor growth and induced alterations in cellular metabolism. ConclusionCombining PTS and RFA may be a promising approach to improve the efficacy of HCC treatment.

Para-Toluene Sulfonamide as an electrolyte additive for dendrite-free Zn metal cells

The aqueous Zinc-ion cells have drawn tremendous attention in the electrochemical energy storage market because of their merits of high safety, environmentally friendly and low cost. However, the high activity of aqueous electrolytes leads to the formation of by-products and the growth of unfavorable dendrites, which seriously reduces the cycling stability of the cell. Herein, an electrolyte additive, Para-Toluene Sulfonamide (PTSA) is introduced to regulate uniform Zn deposition and to suppress side reactions. Due to its own electronegativity, PTSA can guarantee a uniform Zn deposition and form a uniform solid electrode/electrolyte interface (SEI). The symmetric cell of Zn‖Zn with PTSA additive can cycle stability more than 3000 h at 2 mA cm−2. Even increase the current to 15 mA cm−2, the cell still can cycle more than 500 h. The low-cost, promising electrolyte additives discovered in this work provide a new method for high-energy secondary Zn metal cells.

Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to αPD-1 therapy in triple-negative breast cancer

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.

Effects of Para-Toluenesulfonamide on Canine Melanoma Xenotransplants in a BALB/c Nude Mouse Model.

Simple SummaryCanine melanomas are malignant neoplasms, and primary melanomas arise at the footpad, nail bed, gastrointestinal tract, mucocutaneous junction, and eyes. Para-toluenesulfonamide (PTS) is a small molecule that acts against several cancers (hepatocellular carcinoma, nonsmall-cell lung cancer, and tongue squamous cell carcinoma). The pharmacological pathway of PTS has the potential to exert anti-inflammatory and antithrombotic functions. We established canine melanoma xenografts in mice and randomized the animals into four treatment groups: saline, cisplatin, PTS, and PTS combined with cisplatin. The findings indicated that compared with the control mice, mice treated with PTS and the combination of PTS and cisplatin showed retarded tumor growth; increased tumor apoptosis through the upregulation of caspase 3 and extracellular signal-regulated kinase phosphorylation; decreased inflammation levels of cytokines, such as interleukin-1β, tumor necrosis factor-α, and interleukin-6; reduced inflammation-related factors, such as the cyclooxygenase-2 protein and nuclear factor-κB mRNA; enhanced anti-inflammation-related factors; and inhibition of the metastasis-related factors transforming growth factor β, CD44, epidermal growth factor receptor, and vascular endothelial growth factor. Combining cisplatin with PTS has a stronger effect than PTS alone. These findings may prove useful in further explorations of the application of PTS or PTS combined with cisplatin to the treatment of canine melanoma in general.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.

Experimental and computational approach on p-toluenesulfonamide and its derivatives

Spectral analysis of para-toluenesulfonamide (PTS) molecule was experimentally investigated in solid phase by FT-IR, FT-Raman, UV–visible and NMR techniques. The quantum theoretical calculations were performed to predict the bio-activity using the hybrid B3LYP method with the 6-311G (D,P) basis set. The most stable conformer was identified by potential energy surface scan study and the structural parameters were derived from geometry optimization. Normal co-ordinate analysis (NCA) was carried out to perform comprehensive vibrational spectral assignments. The stability ensued due to intramolecular interactions were explained using natural bond orbital (NBO) analysis. The quantum theory of atoms-in-molecules (QTAIM) approach was employed to study various intra-molecular interactions within the molecule. The molecular orbital contributions were studied by using density of states (DOS). Hirshfeld surface analysis explored the nature of interactions present in the molecule. The chemical selectivity or reactivity sites were revealed by using Fukui functions. Molecular docking studies were performed to study the hydrogen bond interactions and the minimum binding energy was calculated.

Para-Toluenesulfonamide Induces Anti-tumor Activity Through Akt-Dependent and -Independent mTOR/p70S6K Pathway: Roles of Lipid Raft and Cholesterol Contents

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.

Effects of para-toluenesulfonamide intratumoral injection on pulmonary adenoid cystic carcinoma complicating with severe central airway obstruction: a 5-year follow-up study.

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.

Effects of para–toluenesulfonamide intratumoral injection on non-small cell lung carcinoma with severe central airway obstruction: A multi-center, non-randomized, single-arm, open-label trial

BackgroundSevere malignant airway obstruction (SMAO) is a life-threatening form of non-small cell lung carcinoma (NSCLC). ObjectivesTo determine the efficacy and safety of para-toluenesulfonamide (PTS) intratumoral injection in NSCLC-SMAO. MethodsNinety 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. ResultsIn 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). ConclusionPTS intratumoral injection is effective and well tolerated for palliative therapy of NSCLC-SMAO.

Para-toluenesulfonamide induces tongue squamous cell carcinoma cell death through disturbing lysosomal stability.

Para-toluenesulfonamide (PTS) has been implicated with anticancer effects against a variety of tumors. In the present study, we investigated the inhibitory effects of PTS on tongue squamous cell carcinoma (Tca-8113) and explored the lysosomal and mitochondrial changes after PTS treatment in vitro. High-performance liquid chromatography showed that PTS selectively accumulated in Tca-8113 cells with a relatively low concentration in normal fibroblasts. Next, the effects of PTS on cell viability, invasion, and cell death were determined. PTS significantly inhibited Tca-8113 cells’ viability and invasive ability with increased cancer cell death. Flow cytometric analysis and the lactate dehydrogenase release assay showed that PTS induced cancer cell death by activating apoptosis and necrosis simultaneously. Morphological changes, such as cellular shrinkage, nuclear condensation as well as formation of apoptotic body and secondary lysosomes, were observed, indicating that PTS might induce cell death through disturbing lysosomal stability. Lysosomal integrity assay and western blot showed that PTS increased lysosomal membrane permeabilization associated with activation of lysosomal cathepsin B. Finally, PTS was shown to inhibit ATP biosynthesis and induce the release of mitochondrial cytochrome c. Therefore, our findings provide a novel insight into the use of PTS in cancer therapy.

Antitumor effect of para-toluenesulfonamide against lung cancer xenograft in a mouse model.

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. 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. 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. 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.

Puncture injection of para-toluenesulfonamide combined with chemoembolization for advanced hepatocellular carcinoma

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.

Gemcitabine plus cisplatin chemotherapy with concurrent para-toluenesulfonamide local injection therapy for peripherally advanced nonsmall cell lung cancer larger than 3 cm in the greatest dimension

Para-toluenesulfonamide (PTS), active ingredient being PTS, is a new anticancer drug applied through local intratumoral injection. The aim of this phase II clinical trial was to investigate the response and toxicity of standard gemcitabine (GEM) plus cisplatin (CIS) chemotherapy with concurrent intratumoral injection of PTS in peripherally advanced nonsmall cell lung cancer. Patients received 1250 mg/m of GEM on day 1, 8, and 75 mg/m of CIS on day 1, every 21 days for four cycles. PTS was injected intratumorally through percutaneous injection under computed tomography guidance on days 5, 12, 15, and 18 of cycle 1, and repeated on days 5 and 12 of cycle 2 if a less than 50% necrotic area was achieved after the first cycle according to the computed tomography scan. Twelve (46.2%) patients had metastatic disease, whereas 14 (53.8%) patients had stage IIIB disease. All 26 patients were assessable for response. Overall response rate by intention-to-treat was 53.8% (95% confidence interval: 34.6-73.0%). Median progression-free survival and overall survival were 6.5 months (95% confidence interval: 3.8-10.2 months) and 14.5 months (10.0-18.0 months), respectively. One-year and 2-year survivals were 57.7 and 22.4%, respectively. The grade 3-4 hematologic adverse events were neutropenia in six patients (23.1%), anemia in three (11.5%), and thrombocytopenia in four patients (15.4%). Nonhematologic toxicities were generally mild and usually not dose-limiting. Although grade 1-2 emesis occurred in nine patients (34.6%), only one had grade 3 vomiting. Grade 1-2 cough, local pain, and peripheral neurotoxocity developed in 12 (46.2%), three (11.5%), and five (19.2%) patients, respectively. There were no treatment-related deaths. GEM/CIS chemotherapy with concurrent PTS local injection therapy is a well-tolerated modality with potential activity in previously untreated peripheral advanced nonsmall cell lung cancer patients.

Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies

To study the in vivo and in vitro metabolism and the effect of para-toluene-sulfonamide (PTS) on cytochrome P450 enzymes (CYP450). Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66+/-0.17 and 0.60+/-0.12 nmol/mg. The K(m) and V(max) were 92.2 micromol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.

Free radical generation is involved in hypoglycemia-induced neuronal death

It is now recognized that neuronal death after hypoglycemia is not a simple result of energy failure resulting from hypoglycemia, but is instead the result of a cell death program that is initiated by hypoglycemia. It will be important to fully understand the sequence of events in this cell death pathway in order to identify late, downstream points at which intervention can be made. A rat model of insulin-induced hypoglycemia was used to assess vesicular zinc release, superoxide production, and the therapeutic potential of a superoxide dismutase (SOD) mimetic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). Hypoglycemia was induced by 15 U/kg insulin injection and terminated by glucose infusion after 30 minutes of isoelectric EEG. Vesicular zinc staining with N (6 methoxy 8 quinolyl) para toluenesulfonamide (TSQ) showed that glucose reperfusion potentiated vesicular zinc release from the hippocampus, and that this release is prevented by the neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7NI). Dihydroethidine (dHEt) detection of superoxide showed superoxide production to be only minimally increased during hypoglycemia, but markedly increased by re-infusion of glucose. This superoxide production was attenuated by intraventricular injection of a zinc chelator, disodium calcium ethylene-diamine tetraaceatic acid (CaEDTA), suggesting that zinc release is upstream event of superoxide production. Treatment with TEMPOL before the glucose reperfusion blocked production of superoxide and reduced neuronal death by more than 60% in hippocampus and cortex when evaluated 1 week after the hypoglycemia. These results suggest that glucose reperfusion-induced vesicular zinc release and subsequent superoxide production are major factors mediating hypoglycemic neuronal death, and that superoxide mimetics can rescue neurons that would otherwise die after severe hypoglycemia. Juvenile Diabetes Research Foundation (SWS, JDRF3-2004-298), Department of Veterans Affairs, and NIH (RAS, NS41421, NS051855-01).

Mutagenicity study of remsen-fahlberg saccharin and contaminants

Saccharin and contaminants of commercial Remsen-Fahlberg saccharin were studied for mutagenic potential with the use of the Salmonella/microsome test, Base-test in Drosophila melanogaster and micronucleus test in mice. In none of these tests were mutagenic effects of saccharin observed. Likewise, the ortho- and para-sulfamoylbenzoic acids (OSBA and PSBA) were ineffective. Para-toluenesulfonamide (PTS) and the major contaminant ortho-toluene-sulfonamide (OTS) exhibited weak mutagenic effects in a modified Salmonella/microsome test and in Drosophila. These results do not indicate mutagenic and therewith correlated carcinogenic potential of saccharin, but they emphasize the possible activity of contaminants.