RESUMEN
Bullous pemphigoid is often difficult to treat with the limited therapies available. Here, we describe clinical outcomes among 30 adults with bullous pemphigoid patients treated with dupilumab. We performed a multicenter, retrospective case series between March 2020 to August 2022. Patients received a loading dose of dupilumab 600 mg, followed by 300 mg maintenance dose with varying administration frequency tailored to individual patient response. All patients experienced at least some improvement in blister formation and pruritus, with 23 (76.7%) of patients demonstrating either complete clearance of blistering or marked response. Complete clearance of pruritus or marked response was noted in 25 (83.3%) of patients. Eight patients were effectively maintained solely on dupilumab. One (3.3%) patient reported an injection site reaction. Thirty patients represent a small sample, however, to our knowledge, this is the second largest group of BP treated with dupilumab. Furthermore, we provide an understandable framework for clinicians outside of academics to follow and assess treatment responses in their BP patients treated with dupilumab. Dupilumab should be considered as a therapeutic option in patients with bullous pemphigoid given its ability to induce sustained blistering and pruritus response in both typical and refractory cases while maintaining a favorable safety profile. J Drugs Dermatol. 2024;23(6):e144-e148. doi:10.36849/JDD.8258e.
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Anticuerpos Monoclonales Humanizados , Penfigoide Ampolloso , Prurito , Humanos , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/diagnóstico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estudios Retrospectivos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Anciano de 80 o más Años , Prurito/tratamiento farmacológico , Prurito/etiología , Prurito/diagnóstico , Adulto , Reacción en el Punto de Inyección/etiología , Reacción en el Punto de Inyección/diagnósticoRESUMEN
Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the ß-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele.
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Arritmias Cardíacas , Canalopatías , Canal de Potasio KCNQ1 , Humanos , Alelos , Arritmias Cardíacas/genética , Proteínas Quinasas Dependientes de AMP Cíclico , Células HEK293 , Canal de Potasio KCNQ1/genética , FenotipoRESUMEN
In the current mpox outbreak, infections are usually self-limited. We describe 3 patients with uncontrolled HIV and mpox infections lasting months, causing debilitating lesions, complications, and death, despite initiating anti-mpox and antiretroviral therapy. Delayed treatment of mpox with antiviral agents may contribute to poor outcomes in severely immunocompromised patients.
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Infecciones por VIH , VIH , Mpox , Humanos , Antivirales/uso terapéutico , Brotes de Enfermedades , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Mpox/complicacionesRESUMEN
INTRODUCTION: Compared with previous geographically localized outbreaks of monkeypox (MPOX), the scale of the 2022 global mpox outbreak has been unprecedented, yet the clinical features of this outbreak remain incompletely characterized. METHODS: We identified patients diagnosed with mpox by polymerase chain reaction (PCR; n = 36) from July to September 2022 at a single, tertiary care institution in the USA. Demographics, clinical presentation, infection course, and histopathologic features were reviewed. RESULTS AND CONCLUSION: Men who have sex with men (89%) and people living with HIV (97%) were disproportionately affected. While fever and chills (56%) were common, some patients (23%) denied any prodromal symptoms. Skin lesions showed a wide range of morphologies, including papules and pustules, and lesions showed localized, not generalized, spread. Erythema was also less appreciable in skin of colour patients (74%). Atypical clinical features and intercurrent skin diseases masked the clinical recognition of several cases, which were ultimately diagnosed by PCR. Biopsies showed viral cytopathic changes consistent with Orthopoxvirus infections. All patients in this case series recovered without complications, although six patients (17%) with severe symptoms were treated with tecovirimat without complication.
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Infecciones por VIH , Mpox , Minorías Sexuales y de Género , Humanos , Masculino , Brotes de Enfermedades , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Homosexualidad Masculina , Mpox/epidemiologíaRESUMEN
AIM: Perioperative bladder catheterization is a controversial issue. Most current recommendations are based on data from open surgery extrapolated to enhanced recovery after surgery or fast-track programmes ranging between 24 and 48 h. The aim of this study is to provide a rationale for reducing catheterization time while at the same time avoiding acute urine retention (AUR), in patients undergoing scheduled laparoscopic colon surgery. METHOD: This is a multicentre, prospective, controlled, randomized non-inferiority study of bladder catheter management in patients undergoing scheduled laparoscopic colon surgery, randomized into two groups: experimental (with catheter removal immediately after surgery) and control (with catheter removal 24 h post-surgery). The main outcome will be the development of AUR, and secondary outcomes the development of urinary infection within the first 30 days and hospital stay. Demographic, surgical and pathological variables will also be evaluated, especially the development of adverse effects assessed according to the Clavien scale and the Comprehensive Complication Index. Following the literature, we assume an incidence of AUR of 11% and a margin of non-inferiority (delta) of 8% and estimate that a sample size of 208 patients per group will be required (with an estimated 10% of losses per group). CONCLUSIONS: In this study we try to demonstrate that the bladder catheter can be removed immediately after scheduled laparoscopic colon surgery, without increasing acute urine retention. This measure would offers the benefits of earlier mobilization and reduces catheter-related morbidity.
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Vejiga Urinaria , Retención Urinaria , Humanos , Vejiga Urinaria/cirugía , Estudios Prospectivos , Cateterismo Urinario/efectos adversos , Retención Urinaria/etiología , Catéteres Urinarios/efectos adversos , Colon/cirugíaRESUMEN
BACKGROUND: Latin American patients in the United States experience significant health disparities. Community health workers (promotoras de salud) reduce disparities by providing culturally appropriate education. While educational interventions have been studied in atopic dermatitis (AD), a chronic dermatologic condition affecting children, none have evaluated the use of promotoras in Spanish-speaking pediatric patients in the United States. OBJECTIVE: To create and evaluate a promotora-led education program for Spanish-speaking caregivers of Latin American, pediatric patients with AD through a randomized, controlled, evaluator-blinded study. METHODS: Children with moderate/severe AD (n = 48) were recruited from the pediatric dermatology clinic at Children's Healthâ in Dallas, TX and randomized to receive clinic education (n = 26) or clinic education plus promotora home visits (n = 22). The primary outcome was overall adherence to topical emollients over the 12-week study, quantified by MEMSCap™ devices; several secondary endpoints were evaluated. RESULTS: Intention-to-treat analysis revealed a trend toward increased overall adherence to emollients over the 12-week study period in promotora (median [interquartile range, IQR]: 43% [26%-61%]) versus non-promotora (median [IQR]: 20% [11%-49%]) (p = .09) groups. SCORAD, AD knowledge, and Spanish-language Parental Quality of Life Questionnaire for AD (Sp-PIQoL-AD) improved in both groups, although there was no statistically significant difference between groups. There was a trend toward increased AD knowledge at Week 4 (p = .06) in the promotora group. CONCLUSIONS: A promotora-led educational intervention is a promising approach in increasing caregiver medication adherence in pediatric, Latin American patients with AD in the United States. Further research using creative and culturally appropriate strategies to increase medication adherence is necessary to reduce health disparities in other racial and ethnic minority populations in the United States.
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Dermatitis Atópica , Humanos , Niño , Estados Unidos , Dermatitis Atópica/tratamiento farmacológico , Emolientes/uso terapéutico , Calidad de Vida , Etnicidad , Agentes Comunitarios de Salud , América Latina , Grupos MinoritariosRESUMEN
PURPOSE: To determine the rate of positivity of immunofluorescence studies in buccal biopsies in patients with cicatrizing conjunctivitis undergoing workup for ocular mucous membrane pemphigoid (MMP)/ocular cicatricial pemphigoid (OCP). DESIGN: Retrospective cohort review. PARTICIPANTS: Forty-one patients with cicatrizing conjunctivitis undergoing workup for OCP. METHODS: A retrospective chart review of direct immunofluorescence (DIF) studies in buccal mucosal biopsies was performed. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of positivity of direct and indirect immunofluorescence studies on buccal mucosal biopsies. RESULTS: Twenty-two patients (54%) had a positive buccal mucosal biopsy; 64% of patients (14/22) demonstrated +DIF on initial biopsy and an additional 36% of patients (8/22) on the second biopsy. Eighteen patients underwent conjunctival biopsy. In the 6 patients with a negative conjunctival biopsy, 4 (67%) had a positive buccal biopsy. CONCLUSIONS: Buccal mucosal immunofluorescence studies may be positive in patients with OCP even in the absence of extraocular disease. Buccal mucosal biopsy may be considered as an alternative to or attempted before conjunctival biopsy for the diagnosis of OCP, particularly in patients in whom conjunctival biopsy may be difficult or imminently visually threatening.
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Conjuntivitis , Penfigoide Benigno de la Membrana Mucosa , Penfigoide Ampolloso , Membrana Basal/patología , Biopsia , Cicatriz , Conjuntiva/patología , Conjuntivitis/diagnóstico , Técnica del Anticuerpo Fluorescente Directa , Humanos , Membrana Mucosa/patología , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Estudios RetrospectivosRESUMEN
INTRODUCTION: Community health workers (CHWs), or promotora de salud, have an important role in healthcare education and advocacy in the Latin American community. We aimed to determine the impact of a promotora de salud program on attitudes and beliefs regarding AD management among Latin American caregivers of pediatric patients with atopic dermatitis. METHODS: This is a sub-study of an ongoing randomized, investigator-blinded, placebo-controlled trial. Mann-Whitney U tests compared questionnaire responses in the standard education group to the promotora group. RESULTS: Caregivers in the promotora group were more likely to state that they knew how to apply wet wraps and use bleach (sodium hypochlorite) baths at 1 month (wet wraps p = .027, bleach baths p = .005) and 3 months (wet wraps p = .005, bleach baths p < .001) demonstrating greater self-efficacy, defined as an individual's belief in their capacity to execute a certain behavior to achieve a desired outcome, compared with the standard education group. CONCLUSIONS: Culturally competent and language concordant educational interventions may improve confidence in utilizing wet wraps and bleach baths among Latin-American caregivers of children with atopic dermatitis, which may improve AD outcomes in the Latin-American community.
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Dermatitis Atópica , Actitud , Cuidadores , Niño , Agentes Comunitarios de Salud , Dermatitis Atópica/terapia , Humanos , LenguajeRESUMEN
The development of new drugs is continuous in the world; currently, saving resources (both economic ones and time) and preventing secondary effects have become a necessity for drug developers. Trichomoniasis is the most common nonviral sexually transmitted infection affecting more than 270 million people around the world. In our research group, we focussed on developing a selective and more effective drug against Trichomonas vaginalis, and we previously reported on a compound, called A4, which had a trichomonacidal effect. Later, we determined another compound, called D4, which also had a trichomonacidal effect together with favorable toxicity results. Both A4 and D4 are directed at the enzyme triosephosphate isomerase. Thus, we made combinations between the two compounds, in which we determined a synergistic effect against T. vaginalis, determining the IC50 and the toxicity of the best relationship to obtain the trichomonacidal effect. With these results, we can propose a combination of compounds that represents a promising alternative for the development of a new therapeutic strategy against trichomoniasis.
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Enfermedades de Transmisión Sexual , Tricomoniasis , Trichomonas vaginalis , Humanos , Enfermedades de Transmisión Sexual/complicaciones , Enfermedades de Transmisión Sexual/tratamiento farmacológico , Relación Estructura-Actividad , Tricomoniasis/complicaciones , Tricomoniasis/tratamiento farmacológico , Triosa-Fosfato Isomerasa/farmacologíaRESUMEN
The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.
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Cardiomiopatía Dilatada , Timopoyetinas , Humanos , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Lamina Tipo A/metabolismo , Leucocitos/metabolismo , Mutación , Mutación Missense , Proteínas Nucleares/genéticaRESUMEN
We present a severe case of acute generalized exanthematous pustulosis (AGEP) secondary to trimethoprim-sulfamethoxazole complicated by non-infectious circulatory shock in a 16-year-old boy. Hemodynamic instability has been reported as a complication of AGEP in adults, but is rarely observed in pediatric patients. The patient we present demonstrated characteristic cutaneous findings of AGEP including isolated non-follicular, sterile pustules on a background of erythema with involvement at intertriginous areas and subsequently developed non-infectious circulatory shock. This case expands the spectrum of possible clinical presentations for AGEP in pediatric patients.
Asunto(s)
Pustulosis Exantematosa Generalizada Aguda , Pustulosis Exantematosa Generalizada Aguda/diagnóstico , Pustulosis Exantematosa Generalizada Aguda/etiología , Adolescente , Adulto , Niño , Humanos , MasculinoRESUMEN
Blastic plasmacytoid dendritic cell neoplasm is a rare hematologic neoplasm originating from plasmacytoid dendritic cell precursors that has an aggressive disease course with typically poor prognosis. Herein, we report a man in his early twenties who presented with rapid onset of violaceous nodules and purpuric papules and macules that began on his chest before spreading to his arms, back, face, scalp, and legs. He also exhibited systemic symptoms including weight loss and night sweats. He was diagnosed with blastic plasmacytoid dendritic cell neoplasm and began treatment with aggressive multidrug therapy. Thus far his treatment has resulted in complete resolution of his cutaneous manifestations.
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Células Dendríticas/patología , Neoplasias Hematológicas/patología , Neoplasias Cutáneas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gangrena de Fournier/inducido químicamente , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Masculino , Neutropenia/inducido químicamente , Neutropenia/complicaciones , Sepsis/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenRESUMEN
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN.
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Síndrome de Stevens-Johnson/terapia , Adulto , HumanosRESUMEN
Severe group A streptococcus (GAS) infections, particularly necrotizing soft tissue infections (NSTIs), have been associated with the development of streptococcal toxic-shock syndrome (STSS), a systemic illness caused by GAS-derived toxins. Traditional physical examination findings in NSTIs include skin necrosis, crepitus, and hemorrhagic bullae. However, these findings are limited in sensitivity and additional clinical markers may aid in making an early diagnosis of NSTI. We present a case of a superficial infection, specifically GAS necrotizing cellulitis, complicated by STSS in a healthy boy with an associated skin finding of retiform purpura that aided in early diagnosis of a NSTI.
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Celulitis (Flemón)/microbiología , Fascitis Necrotizante/microbiología , Púrpura/microbiología , Choque Séptico/microbiología , Infecciones de los Tejidos Blandos/microbiología , Infecciones Estreptocócicas/microbiología , Antibacterianos/uso terapéutico , Celulitis (Flemón)/tratamiento farmacológico , Niño , Diagnóstico Diferencial , Fascitis Necrotizante/tratamiento farmacológico , Humanos , Masculino , Púrpura/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus pyogenes/aislamiento & purificaciónRESUMEN
Plasmablastic lymphoma (PBL) is a rare and aggressive malignancy associated with immunosuppression and the oncogenic effects of the Epstein-Barr virus (EBV). We present an HIV-positive man with PBL that presented as ulcers and violaceous exophytic nodules on the legs. The clinical features, histologic appearance, and differential diagnosis of this malignancy are briefly reviewed.
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Infecciones por Virus de Epstein-Barr/complicaciones , Seropositividad para VIH/complicaciones , Linfoma Plasmablástico/etiología , Diagnóstico Diferencial , Resultado Fatal , Herpesvirus Humano 4 , Humanos , Masculino , Persona de Mediana Edad , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/patologíaRESUMEN
The global rise in urbanization and industrial activity has led to the production and incorporation of foreign contaminant molecules into ecosystems, distorting them and impacting human and animal health. Physical, chemical, and biological strategies have been adopted to eliminate these contaminants from water bodies under anthropogenic stress. Biotechnological processes involving microorganisms and enzymes have been used for this purpose; specifically, laccases, which are broad spectrum biocatalysts, have been used to degrade several compounds, such as those that can be found in the effluents from industries and hospitals. Laccases have shown high potential in the biotransformation of diverse pollutants using crude enzyme extracts or free enzymes. However, their application in bioremediation and water treatment at a large scale is limited by the complex composition and high salt concentration and pH values of contaminated media that affect protein stability, recovery and recycling. These issues are also associated with operational problems and the necessity of large-scale production of laccase. Hence, more knowledge on the molecular characteristics of water bodies is required to identify and develop new laccases that can be used under complex conditions and to develop novel strategies and processes to achieve their efficient application in treating contaminated water. Recently, stability, efficiency, separation and reuse issues have been overcome by the immobilization of enzymes and development of novel biocatalytic materials. This review provides recent information on laccases from different sources, their structures and biochemical properties, mechanisms of action, and application in the bioremediation and biotransformation of contaminant molecules in water. Moreover, we discuss a series of improvements that have been attempted for better organic solvent tolerance, thermo-tolerance, and operational stability of laccases, as per process requirements.
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Biocatálisis , Contaminantes Ambientales/metabolismo , Lacasa , Biodegradación Ambiental , Ecosistema , Hongos/enzimología , Lacasa/química , Lacasa/metabolismo , Plantas/enzimología , Agua/análisis , Agua/química , Purificación del AguaAsunto(s)
Hidradenitis Supurativa , Sepsis , Humanos , Hidradenitis Supurativa/diagnóstico , Estudios Retrospectivos , Femenino , Masculino , Adulto , Sepsis/epidemiología , Persona de Mediana Edad , Brote de los Síntomas , Adulto Joven , Hospitalización/estadística & datos numéricos , Admisión del Paciente/estadística & datos numéricosRESUMEN
A 19-year-old Caucasian female with adult-onset Still disease (AOSD) presented for evaluation of an acute clinical decompensation and atypical annular papules and plaques with purpura on the lower extremities. A punch biopsy demonstrated histiocytes with engulfed degenerated erythrocytes and lymphocytes, consistent with hemophagocytic lymphohistiocytosis (HLH). HLH, clinically referred to as macrophage activation syndrome, is a rare complication of AOSD and is life-threatening. Relevant clinical, laboratory, and histologic features of this diagnosis are reviewed.
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Linfohistiocitosis Hemofagocítica , Síndrome de Activación Macrofágica , Enfermedad de Still del Adulto , Adulto , Eritrocitos/metabolismo , Eritrocitos/patología , Femenino , Histiocitos/metabolismo , Histiocitos/patología , Humanos , Extremidad Inferior/patología , Linfocitos/metabolismo , Linfocitos/patología , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/metabolismo , Linfohistiocitosis Hemofagocítica/patología , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/metabolismo , Síndrome de Activación Macrofágica/patología , Enfermedad de Still del Adulto/diagnóstico , Enfermedad de Still del Adulto/metabolismo , Enfermedad de Still del Adulto/patologíaRESUMEN
BACKGROUND: The GTPase KRas4B has been utilized as a principal target in the development of anticancer drugs. PDE6δ transports KRas4B to the plasma membrane, where it is released to activate various signaling pathways required for the initiation and maintenance of cancer. Therefore, identifying new small molecules that prevent activation of this GTPase by stabilizing the KRas4B-PDE6δ molecular complex is a practical strategy to fight against cancer. METHODS: The crystal structure of the KRas4B-PDE6δ heterodimer was employed to locate possible specific binding sites at the protein-protein interface region. Virtual screening of Enamine-database compounds was performed on the located potential binding sites to identify ligands able to simultaneously bind to the KRas4B-PDE6δ heterodimer. A molecular dynamics approach was used to estimate the binding free-energy of the complex. Cell viability and apoptosis were measured by flow cytometry. G-LISA was used to measure Ras inactivation. Western blot was used to measure AKT and ERK activation. MIA PaCa-2 cells implanted subcutaneously into nude mice were treated with D14 or C22 and tumor volumes were recorded. RESULTS: According to the binding affinity estimation, D14 and C22 stabilized the protein-protein interaction in the KRas4B-PDE6δ complex based on in vitro evaluation of the 38 compounds showing antineoplastic activity against pancreatic MIA PaCa-2 cancer cells. In this work, we further investigated the antineoplastic cellular properties of two of them, termed D14 and C22, which reduced the viability in the human pancreatic cancer cells lines MIA PaCa-2, PanC-1 and BxPC-3, but not in the normal pancreatic cell line hTERT-HPNE. Compounds D14 and C22 induced cellular death via apoptosis. D14 and C22 significantly decreased Ras-GTP activity by 33% in MIA PaCa-2 cells. Moreover, D14 decreased AKT phosphorylation by 70% and ERK phosphorylation by 51%, while compound C22 reduced AKT phosphorylation by 60% and ERK phosphorylation by 36%. In addition, compounds C22 and D14 significantly reduced tumor growth by 88.6 and 65.9%, respectively, in a mouse xenograft model. CONCLUSIONS: We identified two promising compounds, D14 and C22, that might be useful as therapeutic drugs for pancreatic ductal adenocarcinoma treatment.
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Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/química , Descubrimiento de Drogas/métodos , Humanos , Masculino , Ratones , Ratones Desnudos , Simulación de Dinámica Molecular , Neoplasias Pancreáticas/patología , Multimerización de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/química , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Colorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b. Thus, targeting the KRAS4b-PDEδ complex is a treatment strategy for colorectal cancer. METHODS: Using docking and molecular dynamics simulations coupled to molecular mechanics, the generalized born model and solvent accessibility (MMGBSA) approach to explore protein-ligand stability, we found that the compound ((2S)-N-(2,5-diclorofenil)-2-[(3,4-dimetoxifenil)metilamino]-propanamida), termed C19, bound and stabilized the KRAS4b-PDEδ complex. We investigated whether C19 decreases the viability and proliferation of colorectal cancer cells, in addition to knowing the type of cell death that it causes and if C19 decreases the activation of KRAS4b and their effectors. RESULTS: C19 showed high cytotoxicity in the colorectal cancer cell lines HCT116 and LoVo, with a stronger effect in KRAS-dependent LoVo cells. Importantly, C19 significantly decreased tumor size in a xenograft mouse model and showed lower side effects than 5-fluorouracil that is currently used as colorectal cancer treatment. CONCLUSIONS: Mechanistically, the cytotoxic effect was due to increased apoptosis of tumor cells and decreased phosphorylation of Erk and Akt. Therefore, our results suggest that C19 may serve as a promising new treatment for colorectal cancer.