Antitumor action of temozolomide, ritonavir and aprepitant against human glioma cells

Kast, Richard E.; Ramiro, S.; Lladó, Sandra; Toro, Salvador; Coveñas, Rafael; Muñoz, Miguel

doi:10.1007/s11060-015-1996-6

Cited by 45 publications

(54 citation statements)

References 45 publications

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“…The exact mechanism through which NFV promotes glioma inhibition and survival is not well established (Kast & Halatsch, ). An antiviral drug that inhibits MMPs, ritonavir, also shows some efficacy in glioblastoma patients (Kast et al, ). Unfortunately, a phase II clinical trial using ritanovir in association with lopinavir, an antiretroviral of the protease inhibitor class, showed minimal clinical activity in patients with recurrent glioma (Ahluwalia et al, ).…”

Section: Therapeutic Approaches Focused On Ecm and Invasionmentioning

confidence: 99%

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Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

166

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An outstanding characteristic of gliomas is their infiltration into brain parenchyma, a property that impairs complete surgical resection; consequently, these tumors might recur, resulting in a high mortality rate. Gliomas invade along preferential routes, such as those along white matter tracts and in the perineuronal and perivascular spaces. Brain extracellular components and their partners and modulators play a crucial role in glioma cell invasion. This review presents an extensive survey of the literature, showing how the brain extracellular matrix (ECM) is modulated during the glioma infiltration process. We explore aspects of ECM interaction with glioma cells, reviewing the main glycosaminoglycans, glycoproteins and proteoglycans. We discuss the roles of ECM-binding proteins, including CD44, RHAMM, integrins and axonal guidance molecules, and highlight the role of proteases and glycosidases in glioma infiltration; in binding and release chemokines, cytokines and growth factors; and in generating new bioactive ECM fragments. We also consider the roles of cytoskeletal signaling, angiogenesis, miRNAs and the glial-to-mesenchymal transition linked to glioma invasion. We closely discuss therapeutic approaches based on the modulation of the extracellular matrix, targeting the control of glioma infiltration, its relative failure in clinical trials, and potential means to overcome this difficulty.

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Section: Therapeutic Approaches Focused On Ecm and Invasionmentioning

confidence: 99%

“…The exact mechanism through which NFV promotes glioma inhibition and survival is not well established (Kast & Halatsch, 2012). An antiviral drug that inhibits MMPs, ritonavir, also shows some efficacy in glioblastoma patients (Kast et al, 2016).…”

Section: Th Er a P Eu Ti C A Pp R Oa Ch Es F Ocu S E D On Ec M An Dmentioning

confidence: 99%

Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

166

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“…In tumor cells, SP through the NK-1R promotes an anti-apoptotic effect as well as proliferation, migration, invasion and metastasis [15,27,29,32,38,39]. Cancer cells express both SP and the NK-1R and it seems that the undecapeptide is involved in an autocrine mechanism that promotes mitogenesis in tumor cells [15,23,30,[40][41][42][43][44][45][46].…”

Section: The Sp/nk-1r System and Cancer: Cell Signaling Pathways Ovementioning

confidence: 99%

“…It is also known that tumor cells overexpress the NK-1R and that this receptor is essential for the viability of these cells [24,[43][44][45]49]. Thus, many data have shown that the NK-1R is a new potential target for the treatment of any type of tumor (both solid and non-solid), because it is known that NK-1R antagonists, via the NK-1R, induce apoptosis in cancer cells [1,15,23,29,32,39,50,51]. In this sense, recent therapeutic strategies in which the SP/NK-1R is involved have shown excellent results.…”

Section: The Sp/nk-1r System and Cancer: Cell Signaling Pathways Ovementioning

confidence: 99%

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

Muñoz

Coveñas

2020

Preprint

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Acute myeloid leukemia (AML) is an incurable hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca ++ overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells.Thus, the SP/NK-1R system is involved in AML and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is up-dated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (> 20 mg/kg/day) for a period of time according to the response to treatment is suggested).

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“…Özellikle bu sonucun ritonavir ve aprepitant arasındaki sinerjik etkiden olduğu rapor edilmiştir (30). Ayrıca beyin tümörü in vivo modelinde de, 3 mg/kg/gün dozundaki aprepitantın beyin tümörü çevresindeki ödemi iyileştirdiği açıklanmıştır (31).…”

Section: Bulgular Veunclassified

Aprepitantın İnsan Glioblastoma U87MG Hücreleri üzerinde Antiproliferatif ve Apoptotik Etkileri

Dikmen¹

2016

Marmara Pharmaceutical Journal

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GİRİŞGliomalar beyin dokusundan kaynaklanan tümörlerdir ve histopatolojik olarak malignite dereceleri farklılık göstermektedir. Dünya Sağlık Örgütü sınıflamasına göre glioblastoma multiforme (evre IV), gliomalar arasında en malign olanı ve en sık görülenidir. Hızlı çoğalma, beyin dokusuna invazyon, nekroz, anjiyogenez, mikrovasküler proliferasyon ve migrasyon gibi agresif özelliklerie sahiptir. Glioblastoma kemoterapisinde yeni tedavi hedefleri geliştirmek için son yıllarda yoğun araştırmalar yapılmaktadır (1, 2). Astrositlerden orjin alan malignant glial hücrelerin oluşturduğu beyin tümörlerinde, hücre nk(nörokinin) reseptörleri, taşikininler (Substans P (SP) ve nörokinin A (nkA) gibi) tarafından uyarılır. Hücre içi uyarı mekanizmaları tetiklenir ve hücrede başta sitokinler olmak üzere çeşitli aracı moleküller salgılanarak, hücre proliferasyonu gerçekleşir. Birçok in vivo ve in vitro ÖZ Glioblastoma multiforme, gliomalar arasında en malign özellikte olup, görülme sıklığı oldukça yüksektir. Hızlı çoğalma, beyin dokusuna invazyon ve migrasyon gibi agresif özelliklere sahiptir. Bu nedenle son yıllarda glioblastoma kemoterapisinde, yeni tedavi hedeflerinin gelişmesini üzerine çalışmalar yoğunlaşmıştır. Substans P, nörokinin-1 (SP/nk-1) reseptör sistemi, kanser gelişimi ve kanser metastazında önemli bir rol oynamaktadır. Bu nedenle nk-1 reseptörleri, glioblastoma tedavisinde ve nk-1 reseptör antagonistlerinin gelişiminde yeni tedavi hedefleri arasında yer almaktadır.Bu çalışmada, klinikte özellikle kemoterapi sırasında antiemetik amaçla kullanılan, bir nk-1 reseptör antagonisti olan aprepitantın, insan malignant glioblastoma U87MG hücre hattında antiproliferatif ve apoptotik etkileri araştırılmıştır. Çalışmada MTT yöntemi ve gerçek zamanlı hücre analiz sistemi (RTCA DP) ile hücre proliferasyon analizleri, anneksin V-PI ve kaspaz 3 flow sitometri analizleri ile de apoptotik etkiler çalışılmıştır. MTT analizine göre aprepitantın konsantrasyon ve zamana artışına bağlı olarak U87MG hücreleri üzerinde sitotoksik etki yaptığı ve U87MG hücre proliferasyonunu azalttığı görülmüştür. Gerçek zamanlı analiz sisteminden elde edilen hücre indeks değerlerine göre de, 50 µM ve üzeri aprepitant konsantrasyonlarında hücre proliferasyonunun azaldığı ve sırasıyla IC 50 değerlerinin 24. saatte 76.9 µM, 48. saatte 62.5 µM ve 72. saatte de 59.2 µM olarak belirlenmiştir. Flow sitometri analiz sonuçlarına göre aprepitantın 24. saatteki erken ve geç apoptotik etkisi konsantrasyon artışına bağlı olarak artış göstermiştir. Özellikle IC 25 ve IC 50 aprepitant değerlerinde aktif kaspaz-3 değeri kontrole göre, az da olsa artmıştır. Sonuç olarak aprepitantın malignant glioblastoma U87MG hücrelerinde önemli antiproliferatif ve apoptotik etkileri belirlenmiş olup, nk-1 reseptör antagonistlerinin yeni bir terapötik hedef olabileceği düşünülmektedir.

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Antitumor action of temozolomide, ritonavir and aprepitant against human glioma cells

Cited by 45 publications

References 45 publications

Glioma infiltration and extracellular matrix: key players and modulators

Glioma infiltration and extracellular matrix: key players and modulators

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

Aprepitantın İnsan Glioblastoma U87MG Hücreleri üzerinde Antiproliferatif ve Apoptotik Etkileri

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