RESUMO
Transcription infidelity (TI) is a mechanism that increases RNA and protein diversity. We found that single-base omissions (i.e., gaps) occurred at significantly higher rates in the RNA of highly allergenic legumes. Transcripts from peanut, soybean, sesame, and mite allergens contained a higher density of gaps than those of nonallergens. Allergen transcripts translate into proteins with a cationic carboxy terminus depleted in hydrophobic residues. In mice, recombinant TI variants of the peanut allergen Ara h 2, but not the canonical allergen itself, induced, without adjuvant, the production of anaphylactogenic specific IgE (sIgE), binding to linear epitopes on both canonical and TI segments of the TI variants. The removal of cationic proteins from bovine lactoserum markedly reduced its capacity to induce sIgE. In peanut-allergic children, the sIgE reactivity was directed toward both canonical and TI segments of Ara h 2 variants. We discovered 2 peanut allergens, which we believe to be previously unreported, because of their RNA-DNA divergence gap patterns and TI peptide amino acid composition. Finally, we showed that the sIgE of children with IgE-negative milk allergy targeted cationic proteins in lactoserum. We propose that it is not the canonical allergens, but their TI variants, that initiate sIgE isotype switching, while both canonical and TI variants elicit clinical allergic reactions.
Assuntos
Alérgenos/genética , Alérgenos/imunologia , Fabaceae/genética , Fabaceae/imunologia , Mudança da Fase de Leitura do Gene Ribossômico , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Albuminas 2S de Plantas/genética , Albuminas 2S de Plantas/imunologia , Adolescente , Anafilaxia/etiologia , Anafilaxia/imunologia , Animais , Antígenos de Plantas/genética , Antígenos de Plantas/imunologia , Arachis/genética , Arachis/imunologia , Bovinos , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Soros Imunes/genética , Soros Imunes/imunologia , Imunoglobulina E/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Amendoim/etiologia , Hipersensibilidade a Amendoim/imunologia , Phaseolus/genética , Phaseolus/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Glycine max/genética , Glycine max/imunologia , Transcrição GênicaRESUMO
BACKGROUND: Our work has been carried out in the context of the therapeutic failure in ovarian carcinoma, which remains the leading cause of death by gynecologic malignancy. In these tumours, recurrence and subsequent acquired chemoresistance constitute major hurdles to successful therapy. Here we studied the interest of a member of the tripentone chemical family, MR22388, for the treatment of chemoresistant ovarian cancer cells. FINDINGS: MR22388 activity has been assessed in vitro on cisplatin-resistant (SKOV3 and IGROV1-R10) ovarian cancer cell lines by conventional analysis, alone or combined to a BH3-mimetic molecule, ABT-737. MR22388 exerts its activity on cisplatin resistant cells, and we showed that it induces a decrease of the Mcl-1 anti-apoptotic protein expression. Considering our previous work demonstrating that the efficiency of Bcl-xL targeting strategies is conditioned to the concomitant inhibition of Mcl-1 we studied the interest of the association of this MR22388 with ABT-737, and showed that this combination was highly cytotoxic in chemoresistant cells. CONCLUSIONS: This work thus opens new perspectives for the use of this promising molecule for the treatment of highly chemoresistant ovarian cancer cells and for sensitization of emerging Bcl-xL targeting strategies such as the use of BH3-mimetic molecules.
RESUMO
Ovarian cancer is the leading cause of death from gynecological malignancies worldwide. Although the majority of tumors initially respond to standard treatments combining surgery and chemotherapy with platinum based chemotherapy, frequent recurrence and subsequent acquired chemoresistance are responsible for the therapeutic failure, leading to an overall 5 years survival rate of 30%. Considering the usual initial sensitivity of the ovarian tumors to chemotherapy, over the past decade efforts have been focused over the past decade to cure ovarian cancer using the currently available chemotherapeutic agents in various combinations, dosages, schedules (durations and/or routes of administration). However, with such a systemic chemotherapeutic approach, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Considerable efforts are implemented to engineer systems capable of ferrying large doses of cytotoxic agents specifically into targeted malignant cells while sparing healthy cells. The purpose of the present review is to index the main targeted colloidal systems used for drug delivery to ovarian tumors. These nanocarriers will be analyzed by citing examples of their use in preclinical development.