RESUMEN
Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-ß signalling. In this study, the role of integrins and TGF-ß signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-ß pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-ß signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.
Asunto(s)
Resistencia a Antineoplásicos , Melanoma , Venenos de Serpiente , Vemurafenib , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Melanoma/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Venenos de Serpiente/farmacología , Integrina beta3/metabolismo , Integrina beta3/genética , Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Integrinas/metabolismo , Integrinas/antagonistas & inhibidores , Integrina alfa5/metabolismo , Integrina alfa5/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Indoles/farmacología , Indoles/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the ß3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvß3 and αIIbß3 are important anticancer targets, most integrin antagonists developed to target the ß3 integrins are highly selective for αvß3 or αIIbß3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic ß3 integrin antagonist. These new antagonists combine a high activity against αvß3 with a moderate affinity for αIIbß3, providing the first evidence for a new approach to integrin targeting in cancer.
RESUMEN
The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Duocarmicinas/farmacología , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas/síntesis química , Duocarmicinas/química , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Tetrahydroisoquinoline (THIQ) is a key structural component in many biologically active molecules including natural products and synthetic pharmaceuticals. Here, we report on the use of transition-metal mediated [2 + 2 + 2] cyclotrimerisation of alkynes to generate tricyclic THIQs with potential to selectively inhibit AKR1C3.
RESUMEN
Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and ß1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvß3 and αvß5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvß6, αvß8, and ß1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the arginine-glycine-aspartate (RGD)-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour-specific identification and therapy.
RESUMEN
Fused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity.
RESUMEN
The integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions: thrombosis, angiogenesis, and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress toward development of antagonists targeting two or more members of the Arg-Gly-Asp (RGD) binding integrins, notably αvß3, αvß5, αvß6, αvß8, α5ß1, and αIIbß3, as anticancer therapeutics.
Asunto(s)
Antineoplásicos/química , Integrinas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Humanos , Integrinas/química , Integrinas/metabolismo , Terapia Molecular Dirigida , Neoplasias/metabolismo , Neoplasias/patología , Oligopéptidos/metabolismo , Conformación ProteicaRESUMEN
A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.
Asunto(s)
Antineoplásicos/síntesis química , Citocromo P-450 CYP1A1/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Indoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Hidrocarburo de Aril Hidroxilasas/metabolismo , Células CHO , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Citocromo P-450 CYP1B1 , Familia 2 del Citocromo P450 , Daño del ADN , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Indoles/química , Indoles/farmacología , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , TransfecciónRESUMEN
PURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.
Asunto(s)
Neoplasias del Colon/enzimología , Sistema Enzimático del Citocromo P-450/metabolismo , Citotoxinas/toxicidad , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/toxicidad , Indoles/metabolismo , Indoles/toxicidad , Animales , Efecto Espectador , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Familia 2 del Citocromo P450 , Citotoxinas/farmacocinética , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Indoles/farmacocinética , Ratones , Distribución Tisular , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Transicionales/tratamiento farmacológico , Citocromo P-450 CYP1A1/metabolismo , Indoles/farmacología , Pirroles/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Biotransformación , Células CHO , Carcinoma de Células Transicionales/enzimología , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cricetinae , Citocromo P-450 CYP1A1/genética , Femenino , Expresión Génica , Humanos , Indoles/metabolismo , Indoles/farmacocinética , Hígado/metabolismo , Dosis Máxima Tolerada , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Pirroles/metabolismo , Pirroles/farmacocinética , Carga Tumoral/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the ß3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment.
RESUMEN
The identification of an agent that is selectively activated by a cytochrome P450 (CYP) has the potential for tissue specific dose intensification as a means of significantly improving its therapeutic value. Towards this goal, we disclose evidence for the pathway of activation of a duocarmycin analogue, ICT2700, which targets CYP1A1 for biological activity.
Asunto(s)
Alquilantes/farmacología , Citocromo P-450 CYP1A1/metabolismo , Citotoxinas/farmacología , Indoles/farmacología , Alquilantes/química , Animales , Biotransformación , Células CHO , Cricetinae , Cricetulus , Citocromo P-450 CYP1A1/genética , Citotoxinas/química , Humanos , Indoles/química , Terapia Molecular Dirigida , Oxidación-ReducciónRESUMEN
CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Indoles/química , Indoles/farmacología , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Productos Biológicos/uso terapéutico , Evaluación Preclínica de Medicamentos , Duocarmicinas , Humanos , Indoles/uso terapéutico , Pirrolidinonas/química , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéuticoRESUMEN
A bidirectional synthesis of the originally proposed structures for the natural products elatenyne and a chloroenyne from Laurencia majuscula is described along with a reassessment of the structures of the halogenated enynes based upon a 13C NMR chemical shift/structure correlation.
Asunto(s)
Alquenos/síntesis química , Alquinos/síntesis química , Furanos/síntesis química , Laurencia/química , Alquenos/química , Alquinos/química , Productos Biológicos/síntesis química , Furanos/química , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
The condensation of a 2-substituted-2-aminoethanol with methyl 2'-formylbiphenyl-2-carboxylate produces only two of the four possible axially chiral 6,7-dihydrodibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-ones (fused oxazolidine lactams), with kinetically controlled diastereoisomer ratios of up to 96 : 4. Within each lactam product the central chirality of the oxazolidine-fused benzylic position C(4b) is relayed to the biaryl axis with unit efficiency, the mis-matching of these stereogenic elements being prohibited due to strain, as predicted by molecular mechanics calculations. Diastereoisomeric lactam pairs can be equilibrated by heating with acid, and under these thermodynamic conditions reversed diastereoisomer ratios of up to 26 : 74 are observed.
Asunto(s)
Lactamas/química , Oxazoles/química , Termodinámica , Cinética , Lactamas/síntesis química , Modelos Químicos , Estructura Molecular , Estereoisomerismo , Factores de TiempoRESUMEN
[reaction: see text] Enamine [2 + 2] cycloadditions can be achieved in useful yields simply by stirring a mixture of an aldehyde, diethylamine, a dialkyl fumarate, and potassium carbonate in acetonitrile at 25 degrees C, conditions that are compatible with the presence of a potential leaving group on the beta-position of the intermediate enamine. Methylation and elimination of the product cyclobutanes completes a mild nonphotochemical route to functionalized cyclobutenes.
RESUMEN
Unsaturated malonates bearing pendant alcohols yield carbocycles tethered to oxygen heterocycles on exposure to manganese(iii) acetate and an appropriate copper(ii) salt.