MEDROXYPROGESTERONE ACETATE INDUCES C6 GLIOMA CHEMOSENSITIZATION VIA ANTIDEPRESSANT-LIKE LYSOSOMAL PHOSPHOLIPIDOSIS/MYELINOSIS IN VITRO

The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lys...

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Published in:International journal of neuroscience 2007-10, Vol.117 (10), p.1465-1480
Main Authors: ALTINOZ, MERIC A., GEDIKOGLU, GUNDUZ, SAV, AYDIN, OZCAN, EMIN, OZDILLI, KURSAT, BILIR, AYHAN, DEL MAESTRO, ROLANDO F.
Format: Article
Language:English
Subjects:
Animals
Antidepressive Agents
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic Agents - pharmacology
Antineoplastic Agents, Hormonal - pharmacology
Apoptosis - drug effects
Brain Neoplasms - drug therapy
Brain Neoplasms - pathology
Cell Line, Tumor
Cell Nucleus - drug effects
Cell Nucleus - ultrastructure
chemotherapy
Cisplatin - pharmacology
Drug Resistance, Neoplasm
glioma
Glioma - drug therapy
Glioma - pathology
In Vitro Techniques
Lysosomes - drug effects
Lysosomes - metabolism
Lysosomes - ultrastructure
medroxyprogesterone
Medroxyprogesterone Acetate - pharmacology
Methotrexate - pharmacology
Microscopy, Electron
Myelin Sheath - drug effects
Myelin Sheath - metabolism
Myelin Sheath - ultrastructure
Phospholipids - metabolism
S Phase - drug effects
Thymidine - metabolism
Tumor Stem Cell Assay
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Summary:The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lysosomal-phospholipidosis. Exact patterns of myelinosis accompanying to MPA chemo-sensitization is important, because uncoupling of nuclear versus mitochondrial toxicity of anti-neoplastics by MPA would lead to safer employment of glioma chemotherapy with reduced neurotoxicity. By monitoring and comparing cell kinetics with fine structural features of cell death, the authors estimated subcellular effects accompanying growth-inhibitory drug actions in C6 glioma. The analysis revealed that MPA induced mainly lysosomal phospholipidosis, while inhibiting clonogenicity alone and augmenting procarbazine efficacy. It induced apoptosis in combination with cisplatin. It reduced mitochondrial-damage-based early cytotoxicity of methotrexate, yet it did not hinder its anti-clonogenic efficacy. Progesterone analogues-similar to antidepressants-inhibit cholesterol esterification, and this efficacy relates with their P-glycoprotein inhibition. Reducing esterification and plasma-membrane localization of cholesterol may lead MPA induction of lysosomal phospholipidosis, growth indolency, and drug sensitization in glioma.
ISSN:0020-7454
1563-5279
1543-5245
DOI:10.1080/00207450701540062