Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells

Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum–DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC[subscript 50] = 171–443 μmol/L), with maximum cytotoxicity in HOP-62 non–small cell lung cancer cells after 72 hours (IC[subscript 50] = 24 μmol/L). Pyriplatin caused a G[subscript 2]-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin–DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use

The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

BACKGROUND: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. METHODS AND RESULTS: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. CONCLUSION: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression

MISpheroID: a knowledgebase and transparency tool for minimum information in spheroid identity

Spheroids are three-dimensional cellular models with widespread basic and translational application across academia and industry. However, methodological transparency and guidelines for spheroid research have not yet been established. The MISpheroID Consortium developed a crowdsourcing knowledgebase that assembles the experimental parameters of 3,058 published spheroid-related experiments. Interrogation of this knowledgebase identified heterogeneity in the methodological setup of spheroids. Empirical evaluation and interlaboratory validation of selected variations in spheroid methodology revealed diverse impacts on spheroid metrics. To facilitate interpretation, stimulate transparency and increase awareness, the Consortium defines the MISpheroID string, a minimum set of experimental parameters required to report spheroid research. Thus, MISpheroID combines a valuable resource and a tool for three-dimensional cellular models to mine experimental parameters and to improve reproducibility. © 2021, The Author(s)

Molecular and pathological signatures of epithelial–mesenchymal transitions at the cancer invasion front

Reduction of epithelial cell–cell adhesion via the transcriptional repression of cadherins in combination with the acquisition of mesenchymal properties are key determinants of epithelial–mesenchymal transition (EMT). EMT is associated with early stages of carcinogenesis, cancer invasion and recurrence. Furthermore, the tumor stroma dictates EMT through intensive bidirectional communication. The pathological analysis of EMT signatures is critically, especially to determine the presence of cancer cells at the resection margins of a tumor. When diffusion barriers disappear, EMT markers may be detected in sera from cancer patients. The detection of EMT signatures is not only important for diagnosis but can also be exploited to enhance classical chemotherapy treatments. In conclusion, further detailed understanding of the contextual cues and molecular mediators that control EMT will be required in order to develop diagnostic tools and small molecule inhibitors with potential clinical implications

ACTIVITE ANTITUMORALE DE L'OXALIPLATINE ET DE SES COMBINAISONS A D'AUTRES AGENTS CYTOTOXIQUES ANTIMETABOLITES (5-FLUOROURACILE / GEMCITABINE/PEMETREXED DISODIUM) ET INHIBITEURS DE LA TOPOISOMERASE I (SN38/IRINOTECAN)

LE CISPLATINE ET LE CARBOPLATINE FIGURENT DEPUIS PLUS DE 30 ANS PARMI LES MEDICAMENTS LES PLUS ACTIFS DE CHIMIOTHERAPIE ANTICANCEREUSE. CEPENDANT, L'EXISTENCE D'UNE RESISTANCE PRIMAIRE OU ACQUISE A CES MEDICAMENTS CONSTITUE UNE DES RAISONS MAJEURES D'ECHEC THERAPEUTIQUE DANS DE NOMBREUX CAS DE CANCERS. L'OXALIPLATINE EST UN NOUVEAU COMPOSE CONSTITUE D'UN NOYAU CENTRAL DE PLATINE ASSOCIE DE PART ET D'AUTRE A UN RADICAL DIAMINOCYCLOHEXANE ET UN GROUPEMENT OXALATE. CES CARACTERISTIQUES LUI CONFERENT DES PROPRIETES ANTICANCEREUSES UNIQUES QUI LE DISTINGUENT DU CISPLATINE. NOTRE OBJECTIF A ETE DE CARACTERISER LES PROPRIETES ANTIPROLIFERATIVES ET ANTITUMORALES DE L'OXALIPLATINE SEUL ET EN ASSOCIATION AVEC D'AUTRES COMPOSES ANTICANCEREUX. CETTE ACTIVITE A ETE EXPLOREE RESPECTIVEMENT SUR DES LIGNEES CELLULAIRES DE CANCERS HUMAINS, SUR DES CULTURES PRIMAIRES DE CELLULES TUMORALES OBTENUES A PARTIR DE PRELEVEMENTS BIOPSIQUES PROVENANT DIRECTEMENT DE PATIENTS PORTEURS DE CANCERS, AINSI QUE SUR DES XENOGREFFES DE TUMEURS HUMAINES. NOUS AVONS MONTRE QUE IN VITRO, L'OXALIPLATINE EST ACTIF SUR DES TUMEURS HUMAINES D'ORIGINE COLIQUE, MAMMAIRE ET OVARIENNE AINSI QUE SUR DE NOMBREUSES TUMEURS HUMAINES EN CULTURE PRIMAIRE. L'EFFET DE L'OXALIPLATINE EST DEPENDANT IN VITRO DE LA DUREE D'EXPOSITION. LA RESISTANCE AU CISPLATINE ET A D'AUTRES MEDICAMENTS EVALUEE SUR UN ENSEMBLE DE TUMEURS HUMAINES SEMBLE AVOIR PEU D'INFLUENCE SUR L'EFFET ANTIPROLIFERATIF DE L'OXALIPLATINE QUI APPARAIT MAINTENU. L'EFFET ANTIPROLIFERATIF DE L'OXALIPLATINE EST DU A UNE INHIBITION DE LA SYNTHESE DE L'ADN. A CONCENTRATIONS EQUITOXIQUES, L'OXALIPLATINE INDUIT UNE QUANTITE D'ADDUITS DE L'ADN INFERIEUR AU CISPLATINE. CONTRAIREMENT AU CISPLATINE, LES DEFICITS DU SYSTEME DE MESAPPARIEMENT DES BASES AFFECTENT PEU L'EFFET CYTOTOXIQUE DE L'OXALIPLATINE. IN VITRO ET IN VIVO, NOUS AVONS MONTRE QUE LES EFFETS ANTICANCEREUX DE L'OXALIPLATINE SONT OPTIMISES PAR L'UTILISATION CONCOMITANTE OU SEQUENTIELLE D'AUTRES AGENTS ANTICANCEREUX CYTOTOXIQUES APPARTENANT A LA CLASSE DES ANTI-METABOLITES (5-FLUOROURACILE ET GEMCITABINE) ET INHIBITEURS DE TOPO-ISOMERASE I DERIVE DE CAMPTOTECINE (SN38 IN VITRO ET IRINOTECAN IN VIVO). L'OPTIMISATION DE L'EFFET ANTITUMORAL DE L'OXALIPATINE AVEC LE 5 FLUORO-URACILE EST OBTENU LORS D'UNE EXPOSITION SIMULTANEE ALORS QUE DANS LE CAS DE COMBINAISONS AVEC LA GEMCITABINE ET LE SN38 (IRINOTECAN) LA SEQUENCE D'EXPOSITION JOUE UN ROLE CRUCIAL. LES APPLICATIONS THERAPEUTIQUES QUI DECOULENT DE CES ETUDES SONT NOMBREUSES. L'EFFET DE L'OXALIPLATINE SUR LES TUMEURS COLORECTALES, OVARIENNES ET MAMMAIRES SONT PARTICULIEREMENT INTERESSANTES. CES ETUDES ONT PERMIS D'ORIENTER LES ESSAIS THERAPEUTIQUES VERS LES TUMEURS LES PLUS SENSIBLES ET A AIDE AU DESSIN DE PROTOCOLES D'ADMINISTRATION SUR DES BASES RATIONNELLES. LA POTENTIALISATION DE L'EFFET ANTITUMORAL ENTRE L'OXALIPLATINE, LE 5-FLUOROURACILE, LES INHIBITEURS DE TOPO-ISOMERASE I ET LA GEMCITABINE A ETE EXPLOITE LORS D'ETUDES CLINIQUES DE PHASE I-II.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF