Autophagy
Autophagy
Malignant gliomas, among which glioblastomas constitute the largest group, are characterized by a dramatically diffuse infiltration into the brain parenchyma with, as a consequence, the fact that no patient with glioblastoma multi-forme (GBM) has been cured to date. Migrating GBM cells are resistant to apoptosis (Type I programmed cell death), and thus to radiotherapy and conventional chemotherapy, because of the constitutive activation of several intracellular signaling pathways, of which the most important identified to date are the pathways controlled by phosphatidylinositol 3-kinase, Akt, and the mammalian target of rapamycin (mTOR). Migrating GBM cells seem to be less prone to resist autophagy (Type II programmed cell death), and disruption of the pathway controlled by mTOR induces marked autophagic processes in GBM cells. Temozolomide is the most efficacious cytotoxic drug employed today to combat glioblastoma, and this drug exerts its cytotoxic activity through proautophagic processes. Thus, autophagy represents a kind of Trojan horse that can be used to bypass, at least partly, the dramatic resistance of glioblastoma to radiotherapy and proapoptotic-related chemotherapy.
Gliomas account for more than 50% of all brain tumors and are by far the most common primary brain tumors in adults. They include three histopathological subgroups characterized by different levels of aggressiveness and malignancy: ependymomas (< 10% of all gliomas), oligodendrogliomas (10-30%), and astrocytomas (60-70%). All glial tumors are malignant, except for the following: benign ependymomas, subependymomas, gangliocytomas, dysembryoplastic neuroectodermal tumors, subependymal giant-cell astrocytomas, and nodular pilocytic astrocytomas, which taken together account for less than 10% of glial tumors. Malignant astrocytic gliomas are associated with dismal prognoses because of their ability to infiltrate diffusely into the normal brain parenchyma. These so-called "diffuse" astrocytic gliomas include tumors categorized by the World Health Organization as Grades II, III, and IV. Glioblastomas multiforme (Grade IV) account for approximately 50% of all glial tumor types and are associated with the worst prognoses. Patients with these tumors have an average life expectancy of 1 year with the standard treatment of resection followed by radiotherapy. However, an international clinical trial conducted by Stupp, et al., has recently revealed that the addition of the chemotherapy agent temozolomide to radiation therapy increases survival in patients with glioblastoma. A companion laboratory study published by Hegi, et al., has offered hope of even greater improvements in survival in the future, through identification of a molecular change in the tumor that allows the prediction of benefit from the new treatment. The combined work published by Stupp, et al., and Hegi, et al., is therefore being seen as a significant breakthrough in medical research for patients with glioblastoma. These clinical data strongly suggest that delivering temozolomide to patients with glioblastoma as soon as radiotherapy begins, instead of administering temozolomide after radiotherapy once the glioblastoma recurs, has a significant impact on patient survival. Indeed, the 2-year survival rate of patients with glioblastoma who benefitted from conventional treatment is lower than 10%, whereas it exceeds 20% in the series of patients treated by Stupp and colleagues. Temozolomide is a proautophagic drug, not a proapoptotic one. Glioblastomas naturally resist apoptosis. We thus review the following in the present paper: 1) the major signaling pathways that make glioblastomas resistant to apoptosis and, in parallel, the potential association of antimigratory compounds with proapoptotic cytotoxic drugs; 2) the signaling pathways distinctly activated by proautophagic drugs compared with proapoptotic ones; 3) the major scientific data already obtained by researchers to prove that temozolomide is actually a proautophagic drug that overcomes glioblastoma cell resistance to apoptosis; and 4) the most convincing clinical data obtained to date with respect to temozolomide in the treatment of patients with glioblastoma.
Abstract and Introduction
Abstract
Malignant gliomas, among which glioblastomas constitute the largest group, are characterized by a dramatically diffuse infiltration into the brain parenchyma with, as a consequence, the fact that no patient with glioblastoma multi-forme (GBM) has been cured to date. Migrating GBM cells are resistant to apoptosis (Type I programmed cell death), and thus to radiotherapy and conventional chemotherapy, because of the constitutive activation of several intracellular signaling pathways, of which the most important identified to date are the pathways controlled by phosphatidylinositol 3-kinase, Akt, and the mammalian target of rapamycin (mTOR). Migrating GBM cells seem to be less prone to resist autophagy (Type II programmed cell death), and disruption of the pathway controlled by mTOR induces marked autophagic processes in GBM cells. Temozolomide is the most efficacious cytotoxic drug employed today to combat glioblastoma, and this drug exerts its cytotoxic activity through proautophagic processes. Thus, autophagy represents a kind of Trojan horse that can be used to bypass, at least partly, the dramatic resistance of glioblastoma to radiotherapy and proapoptotic-related chemotherapy.
Introduction
Gliomas account for more than 50% of all brain tumors and are by far the most common primary brain tumors in adults. They include three histopathological subgroups characterized by different levels of aggressiveness and malignancy: ependymomas (< 10% of all gliomas), oligodendrogliomas (10-30%), and astrocytomas (60-70%). All glial tumors are malignant, except for the following: benign ependymomas, subependymomas, gangliocytomas, dysembryoplastic neuroectodermal tumors, subependymal giant-cell astrocytomas, and nodular pilocytic astrocytomas, which taken together account for less than 10% of glial tumors. Malignant astrocytic gliomas are associated with dismal prognoses because of their ability to infiltrate diffusely into the normal brain parenchyma. These so-called "diffuse" astrocytic gliomas include tumors categorized by the World Health Organization as Grades II, III, and IV. Glioblastomas multiforme (Grade IV) account for approximately 50% of all glial tumor types and are associated with the worst prognoses. Patients with these tumors have an average life expectancy of 1 year with the standard treatment of resection followed by radiotherapy. However, an international clinical trial conducted by Stupp, et al., has recently revealed that the addition of the chemotherapy agent temozolomide to radiation therapy increases survival in patients with glioblastoma. A companion laboratory study published by Hegi, et al., has offered hope of even greater improvements in survival in the future, through identification of a molecular change in the tumor that allows the prediction of benefit from the new treatment. The combined work published by Stupp, et al., and Hegi, et al., is therefore being seen as a significant breakthrough in medical research for patients with glioblastoma. These clinical data strongly suggest that delivering temozolomide to patients with glioblastoma as soon as radiotherapy begins, instead of administering temozolomide after radiotherapy once the glioblastoma recurs, has a significant impact on patient survival. Indeed, the 2-year survival rate of patients with glioblastoma who benefitted from conventional treatment is lower than 10%, whereas it exceeds 20% in the series of patients treated by Stupp and colleagues. Temozolomide is a proautophagic drug, not a proapoptotic one. Glioblastomas naturally resist apoptosis. We thus review the following in the present paper: 1) the major signaling pathways that make glioblastomas resistant to apoptosis and, in parallel, the potential association of antimigratory compounds with proapoptotic cytotoxic drugs; 2) the signaling pathways distinctly activated by proautophagic drugs compared with proapoptotic ones; 3) the major scientific data already obtained by researchers to prove that temozolomide is actually a proautophagic drug that overcomes glioblastoma cell resistance to apoptosis; and 4) the most convincing clinical data obtained to date with respect to temozolomide in the treatment of patients with glioblastoma.
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