Compound Kills Chemotherapy-resistant Cancer Cells / Il composto uccide le cellule tumorali resistenti alla chemioterapia
Compound Kills Chemotherapy-resistant Cancer Cells / Il composto uccide le cellule tumorali resistenti alla chemioterapia
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
The administration of the compound 10580 caused human GICs (red) transplanted in mice to undergo apoptosis, a type of cell death (green). / La somministrazione del composto 10580 ha fatto sì che GIC umani (rossi) trapiantati nei topi subissero l'apoptosi, un tipo di morte cellulare (verde).Credit: Hokkaido University
A compound effective in killing chemotherapy-resistant glioblastoma-initiating cells (GICs) has been identified, raising hopes of producing drugs capable of eradicating refractory tumors with low toxicity.
Despite longstanding and earnest endeavors to develop new remedies, the prognosis of most glioblastoma patients undergoing chemotherapies and radiotherapies remains poor. Glioblastoma, a malignant glioma, has a median survival period of approximately 15 months. One of the reasons for this is the lack of methods to eradicate its cancer stem cells, or glioblastoma-initiating cells (GICs), that demonstrate tumorigenicity (ability to form tumors) and resistance to chemotherapies and radiotherapies.
In a study published in Neuro-Oncology, the collaborative research group between Hokkaido University, FUJIFILM Corporation, and the National Institute of Advanced Industrial Science and Technology (AIST) successfully cultured human GICs resistant to temozolomide (TMZ), a standard drug used for treating glioblastoma. Next, using Fujifilm's compound library, they conducted a high-throughput drug screening to identify a compound that can specifically kill or inflict damage to GICs, not normal cells such as neural stem cells and astrocytes. The efficacy of the candidate compounds was examined using cytotoxic activities, expressions of various cell markers, and tumor-suppressive activities as indicators.
Compound 10580 was successfully identified as being capable of killing or inflicting damages to GICs. The research group identified that the compound inhibited the activity of dihydroorotate dehydrogenase (DHODH), an essential enzyme for pyrimidine synthesis found in the mitochondria's inner membrane.
While analyzing the compound's efficacy, it was also discovered that the compound decreased the expression of stem cell factors in GICs, unraveling a part of its molecular mechanism. Moreover, the compound was orally administered to tumor-bearing mice, which confirmed its strong anti-cancer efficacy. The mice exhibited no visible toxicity, suggesting that the compound is non-toxic to normal cells.
"Compound 10580 is a promising candidate for developing drugs against glioblastoma and other recurring cancers. Further technological developments of a drug delivery system or 10580 derivatives, which can cross the blood-brain barrier, are needed," says Toru Kondo of Hokkaido University's Institute for Genetic Medicine who led the study.
Despite longstanding and earnest endeavors to develop new remedies, the prognosis of most glioblastoma patients undergoing chemotherapies and radiotherapies remains poor. Glioblastoma, a malignant glioma, has a median survival period of approximately 15 months. One of the reasons for this is the lack of methods to eradicate its cancer stem cells, or glioblastoma-initiating cells (GICs), that demonstrate tumorigenicity (ability to form tumors) and resistance to chemotherapies and radiotherapies.
In a study published in Neuro-Oncology, the collaborative research group between Hokkaido University, FUJIFILM Corporation, and the National Institute of Advanced Industrial Science and Technology (AIST) successfully cultured human GICs resistant to temozolomide (TMZ), a standard drug used for treating glioblastoma. Next, using Fujifilm's compound library, they conducted a high-throughput drug screening to identify a compound that can specifically kill or inflict damage to GICs, not normal cells such as neural stem cells and astrocytes. The efficacy of the candidate compounds was examined using cytotoxic activities, expressions of various cell markers, and tumor-suppressive activities as indicators.
Compound 10580 was successfully identified as being capable of killing or inflicting damages to GICs. The research group identified that the compound inhibited the activity of dihydroorotate dehydrogenase (DHODH), an essential enzyme for pyrimidine synthesis found in the mitochondria's inner membrane.
While analyzing the compound's efficacy, it was also discovered that the compound decreased the expression of stem cell factors in GICs, unraveling a part of its molecular mechanism. Moreover, the compound was orally administered to tumor-bearing mice, which confirmed its strong anti-cancer efficacy. The mice exhibited no visible toxicity, suggesting that the compound is non-toxic to normal cells.
"Compound 10580 is a promising candidate for developing drugs against glioblastoma and other recurring cancers. Further technological developments of a drug delivery system or 10580 derivatives, which can cross the blood-brain barrier, are needed," says Toru Kondo of Hokkaido University's Institute for Genetic Medicine who led the study.
ITALIANO
È stato identificato un composto efficace nell'uccidere le cellule che iniziano il glioblastoma resistente alla chemioterapia (GIC), aumentando le speranze di produrre farmaci in grado di eradicare i tumori refrattari con bassa tossicità.
Nonostante gli sforzi di lunga data e seri per sviluppare nuovi rimedi, la prognosi della maggior parte dei pazienti con glioblastoma sottoposti a chemioterapie e radioterapie rimane scarsa. Il glioblastoma, un glioma maligno, ha un periodo di sopravvivenza mediano di circa 15 mesi. Uno dei motivi di ciò è la mancanza di metodi per sradicare le sue cellule staminali cancerose, o cellule che iniziano il glioblastoma (GIC), che dimostrano la tumorigenicità (capacità di formare tumori) e la resistenza alle chemioterapie e alle radioterapie.
In uno studio pubblicato su Neuro-Oncology, il gruppo di ricerca collaborativa tra l'Università di Hokkaido, la FUJIFILM Corporation e il National Institute of Advanced Industrial Science and Technology (AIST) ha coltivato con successo GIC umani resistenti alla temozolomide (TMZ), un farmaco standard usato per il trattamento glioblastoma. Successivamente, utilizzando la libreria dei composti di Fujifilm, hanno condotto uno screening farmacologico ad alto rendimento per identificare un composto che può specificamente uccidere o infliggere danni ai GIC, non cellule normali come cellule staminali neurali e astrociti. L'efficacia dei composti candidati è stata esaminata usando attività citotossiche, espressioni di vari marcatori cellulari e attività soppressive del tumore come indicatori.
Il composto 10580 è stato identificato con successo come capace di uccidere o infliggere danni ai GIC. Il gruppo di ricerca ha identificato che il composto ha inibito l'attività della diidroorotato deidrogenasi (DHODH), un enzima essenziale per la sintesi di pirimidina presente nella membrana interna dei mitocondri.
Analizzando l'efficacia del composto, è stato anche scoperto che il composto ha ridotto l'espressione dei fattori delle cellule staminali nei GIC, svelando una parte del suo meccanismo molecolare. Inoltre, il composto è stato somministrato per via orale a topi portatori di tumore, confermando la sua forte efficacia anticancro. I topi non hanno mostrato tossicità visibile, suggerendo che il composto non è tossico per le cellule normali.
"Il composto 10580 è un candidato promettente per lo sviluppo di farmaci contro il glioblastoma e altri tumori ricorrenti. Sono necessari ulteriori sviluppi tecnologici di un sistema di rilascio di farmaci o 10580 derivati, che possono attraversare la barriera emato-encefalica", afferma Toru Kondo dell'Istituto universitario di Hokkaido per Medicina genetica che ha guidato lo studio.
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