title: The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells.
abstract: Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12-15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells.
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA, 30322, United States of America.
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA, 30322, United States of America.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Patel
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA, 30322, United States of America.
authors.forename: Seema
authors.initials: S
authors.lastname: Yousuf
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, Atlanta, GA, 30322, United States of America.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000096:biosynthesis; D045643:DNA Repair Enzymes / Q000096:biosynthesis; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011374:Progesterone / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; D018906:Antineoplastic Agents, Alkylating; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D011374:Progesterone; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D045643:DNA Repair Enzymes; D000077204:Temozolomide