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Medicinas Complementárias
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1.
ACS Appl Bio Mater ; 7(4): 2205-2217, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38489294

RESUMEN

Colorectal cancer (CRC) is a common and deadly malignancy, ranking second in terms of mortality and third in terms of incidence on a global scale. The survival rates for CRC patients are unsatisfactory primarily because of the absence of highly effective clinical strategies. The efficacy of existing CRC treatments, such as chemotherapy (CT), is constrained by issues such as drug resistance and damage to healthy tissues. Alternative approaches such as photothermal therapy (PTT), while offering advantages over traditional therapies, suffer instead from a low efficiency in killing tumor cells when used alone. In this context, nanostructures can efficiently contribute to a selective and targeted treatment. Here, we combined CT and PTT by developing a nanoplatform based on polydopamine nanoparticles (PDNPs), selected for their biocompatibility, drug-carrying capabilities, and ability to produce heat upon exposure to near-infrared (NIR) irradiation. As a chemotherapy drug, sorafenib has been selected, a multikinase inhibitor already approved for clinical use. By encapsulating sorafenib in polydopamine nanoparticles (Sor-PDNPs), we were able to successfully improve the drug stability in physiological media and the consequent uptake by CRC cells, thereby increasing its therapeutic effects. Upon NIR stimulus, Sor-PDNPs can induce a temperature increment of about 10 °C, encompassing both PTT and triggering a localized and massive drug release. Sor-PDNPs were tested on healthy colon cells, showing minimal adverse outcomes; conversely, they demonstrated excellent efficacy against CRC cells, with a strong capability to hinder cancer cell proliferation and induce apoptosis. Obtained findings pave the way to new synergistic chemo-photothermal approaches, maximizing the therapeutic outcomes against CRC while minimizing side effects on healthy cells.


Asunto(s)
Neoplasias Colorrectales , Hipertermia Inducida , Indoles , Nanopartículas , Polímeros , Humanos , Fototerapia , Terapia Fototérmica , Sorafenib , Nanopartículas/uso terapéutico , Nanopartículas/química , Neoplasias Colorrectales/tratamiento farmacológico
2.
Gene ; 912: 148383, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38493972

RESUMEN

Liver cancer is one of the most lethal malignancies and sorafenib resistance is the main treatment obstacle for patients with advanced liver cancer. Developing drugs that sensitize liver cancer patients to sorafenib is of great importance. Lianhua Qingwen (LHQW), a sort of Traditional Chinese Medicine (TCM) approved by the Chinese Food and Drug Administration (CFDA), is reported to exert synergistic effects with oseltamivir against Influenza virus. However, whether LHQW could exhibit anti-liver cancer effects and enhance the efficacy of sorafenib against liver cancer have not been reported. In the present study, the potential anti-liver cancer effects of LHQW and its synergistic effects with sorafenib were investigated via applying network pharmacology, molecular docking, and in vitro experiments. An "ingredient-compound- target-liver cancer" network was constructed which included 12 ingredients, 164 compounds, and 402 targets. AKT1 was identified as the most hub gene and the PI3K/AKT pathway was revealed as the most enriched pathway. Subsequently, the molecular docking results showed that kaempferol, luteolin, and quercetin were screened as the top 3 compounds which showed the tightest binding to AKT1. Further, the in vitro experiments verified that LHQW significantly inhibited liver cancer cell proliferation and induced apoptosis. Western blot assays confirmed that LHQW could attenuate the PI3K/AKT pathway. Interestingly, LHQW showed a synergistic effect with sorafenib against liver cancer via reducing cell viability, inducing apoptosis, and down- regulating PI3K/AKT pathway. This study broadens the potential application of LHQW and provides insights for liver cancer treatment.


Asunto(s)
Medicamentos Herbarios Chinos , Neoplasias Hepáticas , Humanos , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Sorafenib/farmacología , Farmacología en Red , Neoplasias Hepáticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico
3.
PLoS One ; 19(3): e0295090, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38437209

RESUMEN

BACKGROUND: To evaluate the cost-effectiveness of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma (HCC) from the perspective of the Chinese health service system. METHODS: A lifetime partitioned survival model (PSM) was developed to cost-effectively analyze Tislelizumab vs Sorafenib as the first-line treatment of unresectable HCC. The clinical and safety data were derived from a recently randomized clinical trial (RATIONALE-301). Utilities were collected from the published literature. Costs were obtained from an open-access database (http://www.yaozh.com) and previous studies. The model cycle was 21 days, according to the RATIONALE-301 study, and the simulation period was patients' lifetime. Long-term direct medical costs and quality-adjusted life-years (QALYs) were determined. The incremental cost-effectiveness ratio (ICER) was used as the evaluation index. one-way sensitivity analysis (OSWA) and probabilistic sensitivity analysis (PSA) were used to analyze the uncertainty of parameters and to adjust and verify the stability of the baseline results. RESULTS: The Tislelizumab group generated a cost of $39,746.34 and brought health benefits to 2.146 QALYs, while the cost and utility of the Sorafenib group were $26750.95 and 1.578 QALYs, respectively. The Tislelizumab group increased QALYs by 0.568, the incremental cost was $12995.39, and the ICER was $22869.64/QALY, lower than the willingness to pay threshold (WTP). OSWA results showed that the utility of progressed disease (PD), cost of Camrelizumab, and cost of Tislelizumab were the main factors affecting the ICER. PSA results showed that, within 1000 times the Monte Carlo simulation, the cost of the Tislelizumab group was lower than three times the per capita gross domestic product (GDP) of China ($37653/QALY). The cost-effectiveness acceptability curves (CEAC) revealed that when WTP was no less than $12251.00, the Tislelizumab group was the dominant scheme, and the economic advantage grew with an increasing WTP. When WTP ≥ $19000.00, the Tislelizumab group became the absolute economic advantage. CONCLUSION: Under the current economic conditions in China, the Tislelizumab therapeutic scheme is more cost-effective than the Sorafenib therapeutic scheme for treating patients with unresectable HCC.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Sorafenib/uso terapéutico , Análisis de Costo-Efectividad , Neoplasias Hepáticas/tratamiento farmacológico
4.
Adv Ther ; 41(4): 1711-1727, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38443649

RESUMEN

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.


Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.


Asunto(s)
Encefalopatías , Carcinoma Hepatocelular , Hipertensión Portal , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Incidencia , Neoplasias Hepáticas/tratamiento farmacológico , Estudios Retrospectivos , Sorafenib , Hemorragia
5.
Sci Rep ; 14(1): 5592, 2024 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-38454105

RESUMEN

To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.


Asunto(s)
Anilidas , Carcinoma de Células Renales , Indazoles , Neoplasias Renales , Compuestos de Fenilurea , Piridinas , Pirimidinas , Quinolinas , Sulfonamidas , Anciano , Humanos , Masculino , Axitinib/uso terapéutico , Teorema de Bayes , Carcinoma de Células Renales/tratamiento farmacológico , Electrólitos , Neoplasias Renales/patología , Farmacovigilancia , Estudios Retrospectivos , Sorafenib/efectos adversos , Sunitinib/efectos adversos , Estados Unidos , United States Food and Drug Administration , Femenino , Persona de Mediana Edad
6.
Ecotoxicol Environ Saf ; 273: 116161, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38430581

RESUMEN

Di(2-ethylhexyl) phthalate (DEHP) is a worldwide common plasticizer. Nevertheless, DEHP is easily leached out to the environment due to the lack of covalent bonds with plastic. High dose of DEHP exposure is often observed in hemodialysis patients because of the continual usage of plastic medical devices. Although the liver is the major organ that catabolizes DEHP, the impact of long-term DEHP exposure on the sensitivity of liver cancer to chemotherapy remains unclear. In this study, we established long-term DEHP-exposed hepatocellular carcinoma (HCC) cells and two NOD/SCID mice models to investigate the effects and the underlying mechanisms of long-term DEHP exposure on chemosensitivity of HCC. The results showed long-term DEHP exposure potentially increased epithelial-mesenchymal transition (EMT) in HCC cells. Next generation sequencing showed that long-term DEHP exposure increased cell adhesion/migratory related genes expression and blunted sorafenib treatment induced genes alterations. Long-term exposure to DEHP reduced the sensitivity of HCC cells to sorafenib-induced anti-migratory effect by enhancing the EMT transcription factors (slug, twist, and ZEB1) and mesenchymal protein (vimentin) expression. In NOD/SCID mice model, we showed that long-term DEHP-exposed HCC cells exhibited higher growth rate. Regarding the anti-HCC effects of sorafenib, subcutaneous HuH7 tumor grew slowly in sorafenib-treated mice. Nonetheless, the anti-tumor growth effect of sorafenib was not observed in long-term DEHP-exposed mice. Higher mesenchymal markers and proliferating cell nuclear antigen (PCNA) expression were found in sorafenib-treated long-term DEHP-exposed mice. In conclusion, long-term DEHP exposure promoted migratory activity in HCC cells and decreased sorafenib sensitivity in tumor-bearing mice.


Asunto(s)
Carcinoma Hepatocelular , Dietilhexil Ftalato , Neoplasias Hepáticas , Ácidos Ftálicos , Humanos , Ratones , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Dietilhexil Ftalato/toxicidad , Ratones SCID , Ratones Endogámicos NOD , Resultado del Tratamiento
7.
Drug Des Devel Ther ; 18: 829-843, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38524877

RESUMEN

Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Hipertensión , Neoplasias Renales , Neoplasias Hepáticas , Humanos , Sorafenib/efectos adversos , Carcinoma Hepatocelular/patología , Antineoplásicos/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Niacinamida , Compuestos de Fenilurea/efectos adversos , Neoplasias Hepáticas/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos
8.
Phytomedicine ; 128: 155317, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38537439

RESUMEN

BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC. METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts. RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues. CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.


Asunto(s)
Apoptosis , Carcinoma Hepatocelular , Daño del ADN , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico , Neoplasias Hepáticas , Ratones Desnudos , Especies Reactivas de Oxígeno , Sorafenib , Witanólidos , Witanólidos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Daño del ADN/efectos de los fármacos , Sorafenib/farmacología , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Tiorredoxina Reductasa 1/metabolismo , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Factor de Transcripción Activador 4/metabolismo
9.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38338736

RESUMEN

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.


Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sorafenib/uso terapéutico , Factores de Riesgo
10.
Int J Mol Sci ; 25(3)2024 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-38338842

RESUMEN

Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib-vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors (p < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Sorafenib/farmacología , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/metabolismo , Vinorelbina/farmacología , Neoplasias Hepáticas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
11.
Zhongguo Zhong Yao Za Zhi ; 49(1): 185-196, 2024 Jan.
Artículo en Chino | MEDLINE | ID: mdl-38403351

RESUMEN

This study investigated the effect of trametenolic acid(TA) on the migration and invasion of human hepatocellular carcinoma HepG2.2.15 cells by using Ras homolog gene family member C(RhoC) as the target and probed into the mechanism, aiming to provide a basis for the utilization of TA. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the proliferation of HepG2.2.15 cells exposed to TA, and scratch and Transwell assays to examine the cell migration and invasion. The pull down assay was employed to determine the impact of TA on RhoC GTPase activity. Western blot was employed to measure the effect of TA on the transport of RhoC from cytoplasm to cell membrane and the expression of RhoC/Rho-associated kinase 1(ROCK1)/myosin light chain(MLC)/matrix metalloprotease 2(MMP2)/MMP9 pathway-related proteins. RhoC was over-expressed by transient transfection of pcDNA3.1-RhoC. The changes of F-actin in the cytoskeleton were detected by Laser confocal microscopy. In addition, the changes of cell migration and invasion, expression of proteins in the RhoC/ROCK1/MLC/MMP2/MMP9 pathway, and RhoC GTPase activity were detected. The subcutaneously transplanted tumor model of BALB/c nude mice and the low-, medium-, and high-dose(40, 80, and 120 mg·kg~(-1), respectively) TA groups were established and sorafenib(20 mg·kg~(-1)) was used as the positive control. The tumor volume and weight in each group were measured, and the expression of related proteins in the tumor tissue was determined by Western blot. The results showed that TA inhibited the proliferation of HepG2.2.15 cells in a concentration-dependent manner, with the IC_(50) of 66.65 and 23.09 µmol·L~(-1) at the time points of 24 and 48 h, respectively. The drug administration groups had small tumors with low mass. The tumor inhibition rates of sorafenib and low-, medium-and high-dose TA were 62.23%, 26.48%, 55.45%, and 62.36%, respectively. TA reduced migrating and invading cells and inhibited RhoC protein expression and RhoC GTPase activity in a concentration-dependent manner, dramatically reducing RhoC and membrane-bound RhoC GTPase. The expression of ROCK1, MLC, p-MLC, MMP2, and MMP9 downstream of RhoC can be significantly inhibited by TA, as confirmed in both in vitro and in vivo experiments. After HepG2.2.15 cells were transfected with pcDNA3.1-RhoC to overexpress RhoC, TA down-regulated the protein levels of RhoC, ROCK1, MLC, p-MLC, MMP2, and MMP9 and decreased the activity of RhoC GTPase, with the inhibition level comparable to that before overexpression. In summary, TA can inhibit the migration and invasion of HepG2.2.15 cells. It can inhibit the RhoC/ROCK1/MLC/MMP2/MMP9 signaling pathway by suppressing RhoC GTPase activity and down-regulating RhoC expression. This study provides a new idea for the development of autophagy modulators targeting HSP90α to block the proliferation and inhibit the invasion and migration of hepatocellular carcinoma cells via multiple targets of active components in traditional Chinese medicines.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Humanos , Proteína rhoC de Unión a GTP/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Sorafenib , Ratones Desnudos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Movimiento Celular , Proliferación Celular
12.
Clin Drug Investig ; 44(3): 149-162, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38300386

RESUMEN

BACKGROUND AND OBJECTIVES: Camrelizumab plus rivoceranib showed significant clinical benefits in progression-free survival and overall survival compared to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). This study aimed to assess its cost effectiveness from the perspective of Chinese health care system. METHODS: A Markov state-transition model was developed based on the Phase 3 randomized CARES-310 clinical trial data. Health state utility values were obtained from the CARES-310 clinical trial, and direct medical costs were derived from the relevant literature and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses were performed to assess the uncertainty of the model. RESULTS: In the base-case analysis, the incremental effectiveness and cost of camrelizumab plus rivoceranib versus sorafenib were 0.41 QALYs and $13,684.84, respectively, resulting in an ICER of $33,619.98/QALY, lower than the willingness-to-pay threshold of China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of camrelizumab plus rivoceranib versus sorafenib were $35,920.01 and $29,717.98 in patients with ALBI grade 1 and grade 2, respectively. One-way sensitivity analyses indicated that the cost of camrelizumab, the proportion of patients receiving subsequent treatment in the camrelizumab plus rivoceranib group, and the cost of rivoceranib were the most significant factors in the base-case analysis. Probabilistic sensitivity analysis suggested that the probabilities of cost effectiveness of camrelizumab plus rivoceranib were 61.27%, 51.46%, and 82.78% for any grade, and ALBI grade 1 and grade 2, respectively. CONCLUSIONS: Camrelizumab plus rivoceranib was more cost effective than sorafenib as first-line therapy for unresectable HCC in the Chinese setting.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Neoplasias Hepáticas , Piridinas , Humanos , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Análisis de Costo-Efectividad , Neoplasias Hepáticas/tratamiento farmacológico , Análisis Costo-Beneficio , Atención a la Salud
13.
J Cancer Res Clin Oncol ; 150(2): 81, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38319485

RESUMEN

PURPOSE: The GALAD score and the BALAD-2 score are biomarker-based scoring systems used to detect hepatocellular carcinoma (HCC). Both incorporate levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP). Our objective was to examine the relationship between the GALAD score as well as the BALAD-2 score and treatment response to transarterial or systemic treatments in patients with HCC. METHODS: A total of 220 patients with HCC treated with either transarterial (n = 121) or systemic treatments (n = 99; mainly Sorafenib) were retrospectively analyzed. The GALAD score and the BALAD-2 score were calculated based on AFP-L3, AFP, and DCP levels measured in serum samples collected before treatment. The results were correlated with 3-month treatment efficacy based on radiologic mRECIST criteria. RESULTS: The GALAD score showed a strong correlation with BCLC stage (p < 0.001) and total tumor diameter before treatment (p < 0.001).The GALAD score at baseline was significantly lower in patients with a 3-month response to transarterial (p > 0.001) than in refractory patients. Among patients receiving systemic treatment, the median BALAD-2 score at baseline showed a strong association with response at month 3 (p < 0.001). In the transarterial treatment group, the GALAD score (AUC = 0.715; p < 0.001) as well as the BALAD score (AUC = 0.696; p < 0.001) were associated with overall survival, hereby outperforming AFP, AFP-L3 and DCP. CONCLUSION: The GALAD score as well as the BALAD-2 score hold significant promise as a prognostic tool for patients with early or intermediate-stage HCC who are undergoing transarterial or systemic treatments.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , alfa-Fetoproteínas , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib
15.
Int J Biol Macromol ; 263(Pt 1): 130162, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38365149

RESUMEN

Sorafenib (SF) is a first-line drug for the treatment of hepatocellular carcinoma (HCC) in clinical practice. However, acquired drug resistance tremendously limits the clinical efficacy of sorafenib in treating HCC, which has attracted great attention. PDL1 plays a crucial role in the drug resistance of HCC. Here, a codelivery system based on poly-SS-lysine modified chitosan (TAT-C-SS-P) was established and was applied to deliver sorafenib and PDL1-siRNA for synergetic HCC therapy. The successful synthesis of TAT-C-SS-P was confirmed by 1H NMR. Additionally, sorafenib and PDL1-siRNA were successfully transported into the cells as the decreased expression of VEGF and PD-L1 by administrated with TAT-C-SS-P@SF@ PDL1-siRNA. Simultaneously, the expression of pro-apoptosis proteins cyt-c and Bax was prominently augmented, whereas the expression of anti-apoptosis protein Bcl-2 was decreased. The reduced expression of PDL1 resulted in the downregulation of P-GP and MRP1, which contributed to more sorafenib aggregation in tumor cells. Moreover, TAT-C-SS-P@PDL1-siRNA@SF efficiently promotes apoptosis of HepG2-SI cells, as the apoptosis rate rised to 73 %. A sorafenib-insensitive model was established to evaluate in vivo antitumor effect of TAT-C-SS-P@PDL1-siRNA@SF. TAT-C-SS-P@PDL1-siRNA@SF showed a tumor inhibition rate of 90.2 ± 3.5 % and no significant decrease in body weight. Taken together, our study provided compelling evidence that TAT-C-SS-P@PDL1-siRNA@SF has great potential application in the treatment of HCC clinically.


Asunto(s)
Carcinoma Hepatocelular , Quitosano , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Sorafenib/farmacología , Quitosano/farmacología , Lisina/farmacología , ARN Interferente Pequeño , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Antígeno B7-H1 , Línea Celular Tumoral , Apoptosis , Resistencia a Antineoplásicos/genética , Proliferación Celular
16.
Biomater Sci ; 12(7): 1864-1870, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38411494

RESUMEN

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy and mortality. Sorafenib (SOR), a multi-kinase inhibitor, is clinically used in the treatment of HCC. However, SOR suffers from serious side effects and drug resistance. The development of novel therapeutic strategies for HCC therapy is urgently needed. Sonodynamic therapy (SDT) has unique advantages in treating deep tumors due to the merits of deep tissue penetration, low side effects, and the absence of drug resistance. Here, we developed multifunctional nanoparticles (NPs) termed SOR-TCPP@PEG-FA by assembling SOR, tetrakis (4-carboxyphenyl) porphyrin (TCPP), and folic acid (FA)-modified DSPE-PEG. The FA group enhances the tumor targeting capability of these NPs, while TCPP generates ROS under ultrasound (US) irradiation, which are toxic to tumor cells, and SOR with chemotherapeutic effects is released, thus realizing the synergistic SDT and chemotherapy of tumors.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Porfirinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Sorafenib , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Porfirinas/farmacología , Porfirinas/uso terapéutico , Línea Celular Tumoral
17.
ACS Appl Mater Interfaces ; 16(9): 11239-11250, 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38395769

RESUMEN

Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.


Asunto(s)
Células Estrelladas Hepáticas , Nanopartículas , Ratones , Animales , Cirrosis Hepática/tratamiento farmacológico , Hígado/patología , Sorafenib/uso terapéutico , Albúminas
18.
Medicine (Baltimore) ; 103(3): e36865, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38241568

RESUMEN

BACKGROUND: Apatinib, a novel tyrosine kinase inhibitor independently developed by China, has been widely used in the treatment of advanced hepatocellular carcinoma (HCC) in recent years. For more than a decade, sorafenib has been the classic first-line treatment option for patients with advanced HCC. However, the results of clinical studies comparing the efficacy and safety of these 2 drugs are still controversial. Therefore, the aim of this meta-analysis is to evaluate the efficacy and safety of apatinib versus sorafenib as first-line treatment for advanced HCC. METHODS: Up to August 14, 2023, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and clinical studies of experimental group (apatinib or apatinib plus transarterial chemoembolization [TACE]) versus control group (sorafenib or sorafenib plus TACE) in the first-line treatment of advanced HCC were included. Two researchers evaluated the quality of the included studies and extracted the data. Revman 5.4 software was used for meta-analysis. RESULTS: A total of 12 studies involving 1150 patients were included. Five studies are apatinib alone versus sorafenib alone, and the other 7 studies are apatinib plus TACE versus sorafenib plus TACE. The results of the meta-analysis showed that compared with sorafenib alone, apatinib could improve (OR = 3.06, 95%CI: 1.76-5.31), had no advantage in improving DCR (OR = 1.52, 95%CI: 0.86-2.68) and prolonging PFS (HR = 1.35, 95%CI: 0.94-1.96), and was significantly worse in prolonging OS (HR = 1.43, 95%CI: 1.08-1.88). Similarly, apatinib plus TACE was inferior to sorafenib plus TACE in prolonging OS (HR = 1.15, 95%CI: 1.03-1.28), although it improved ORR (OR = 1.49, 95%CI: 1.03-2.16). In terms of adverse drug events, the overall incidence of adverse events, and the incidence of drug reduction and discontinuation in the experimental group were significantly higher than those in the control group (P < .05). The incidence of hypertension, proteinuria, and oral mucositis in the experimental group was significantly higher than that in the control group (P < .05). CONCLUSION: In the setting of first-line treatment of advanced HCC, apatinib has improved short-term efficacy (ORR) compared with sorafenib, but the safety and long-term efficacy of apatinib are inferior to sorafenib.


Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/patología , Sorafenib/efectos adversos , Sorafenib/uso terapéutico
19.
United European Gastroenterol J ; 12(2): 252-260, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38267015

RESUMEN

The evolution in systemic therapies in hepatocellular carcinoma (HCC) signifies a strategy of high-cost, high-gain innovation that originated with sorafenib, despite its limited impact on tumor response. This strategic approach paved the way for the emergence of a second wave of the short-lived competitive advantage, exemplified by the incorporation of atezolizumab plus bevacizumab and tremelimumab plus durvalumab. In the context of safety concerns within the liver cancer domain, the IMBRAVE150 and HIMALAYA trials boldly incorporated bevacizumab and tremelimumab, respectively, demonstrating the continuation of the high-risk, high-reward innovation paradigm. This review delves into the strengths, weaknesses, opportunities, and threats analysis of systemic therapies in the field of HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Bevacizumab/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico
20.
J Control Release ; 366: 798-811, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38184236

RESUMEN

Oral cancer is a disease with high morbidity and mortality worldwide and greatly impacts the quality of life, especially in patients with advanced stages. Photodynamic therapy (PDT) is one of the most effective clinical treatments for oral cancers. However, most clinically applied photosensitizers have several deficiencies, including oxygen dependence, poor aqueous solubility, and a lack of tumor-targeting ability. Herein, the carrier-free multifunctional Sorafenib (Sor), chlorin e6 (Ce6), and Fe3+ self-assembly co-delivery nanoparticles (Sor-Ce6 NPs) were constructed via combining a ferroptosis inducer Sor and a photosensitizer Ce6 for synergetic therapy. The as-synthesized Sor-Ce6 NPs presented excellent colloidal stability and water dispersity with good in vivo tumor-targeting ability. More significantly, the low dose of Sor-Ce6 NPs had little dark toxicity but produced significantly enhanced ROS and supplied O2 sustainably to increase phototoxicity through ferroptosis pathway. Notably, the Sor-Ce6 NPs showed significantly higher in vitro and in vivo anti-tumor efficacy than the Sor/Ce6 mixture due to the improvement of cellular uptake and the incorporation of foreign Fe ions in the system, which also confer the T1 magnetic resonance-guided imaging ability to the formed Sor-Ce6 NPs. Our study demonstrates a promising self-assembled strategy for overcoming hypoxia-related PDT resistance for oral cancer treatment.


Asunto(s)
Clorofilidas , Ferroptosis , Neoplasias de la Boca , Nanopartículas , Fotoquimioterapia , Porfirinas , Humanos , Sorafenib , Calidad de Vida , Neoplasias de la Boca/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Línea Celular Tumoral
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