Abstract
Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months.Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ.The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy.The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models.The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB.In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM.Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy.Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments.In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy.
Highlights
The results demonstrated that glioblastoma multiforme (GBM) cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on Blood Brain Barrier (BBB)
Basing on literature data regarding the pharmacological modulation of BBB by morphine [17], the most commonly used opioid in oncological patients, we have recently demonstrated that this agent is able to increase delivery and efficacy of doxorubicin (Dox) in animal models, without increasing systemic toxicities [18, 19, 20, 21]
The development of combination therapy that could sensitize GBM to TMZ is essential so, the aim of the present study was investigate the potential of an innovative combinational approach with morphine to improve chemotherapy effectiveness, reducing drug dosage and TMZ-induced side effects
Summary
GBM is the most common and aggressive primary brain tumor derived from glial progenitors of the central nervous system (CNS) [1, 2].TMZ, the current standard care for GBM [3, 4], shows chemoresistance shortly after the initiation of treatment [5]; patients median survival is about 12–18 months and only 3 % survive longer than 5 years [6].www.impactjournals.com/oncotargetResistance to TMZ has shown to be multifactorial, including changes in the cell cycle, up regulation of mismatch repair genes and MGMT [7] and additional TMZ resistance mechanisms involving P-gp expression, modulation and activity have been recently reported [8, 9, 10].P-gp belongs to the ATP binding cassette (ABC) transporters and plays the major role in the failure of cancer therapy, limiting the accumulation of a wide range of molecules in numerous tissue including the brain [11].Different studies have shown that brain concentrations of TMZ are only 17–20 % of the blood levels [12, 13] and TMZ’s dose limiting toxicity of leukopenia and thrombocytopenia, with a possible increased risk of opportunistic infections, precludes the use of higher doses which theoretically could result in higher intratumoral concentrations.It was reported that antitumor activity of TMZ is highly schedule-dependent [14, 15]; many experimental and preclinical studies suggested that in vivo frequent administration of low doses of chemotherapeutic drugs, known as metronomic chemotherapy, could affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects [16].Basing on literature data regarding the pharmacological modulation of BBB by morphine [17], the most commonly used opioid in oncological patients, we have recently demonstrated that this agent is able to increase delivery and efficacy of doxorubicin (Dox) in animal models, without increasing systemic toxicities [18, 19, 20, 21]. Resistance to TMZ has shown to be multifactorial, including changes in the cell cycle, up regulation of mismatch repair genes and MGMT [7] and additional TMZ resistance mechanisms involving P-gp expression, modulation and activity have been recently reported [8, 9, 10]. Different studies have shown that brain concentrations of TMZ are only 17–20 % of the blood levels [12, 13] and TMZ’s dose limiting toxicity of leukopenia and thrombocytopenia, with a possible increased risk of opportunistic infections, precludes the use of higher doses which theoretically could result in higher intratumoral concentrations.
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