Progesterone Is More Effective Than Dexamethasone in Prolonging Overall Survival and Preserving Neurologic Function in Experimental Animals with Orthotopic Glioblastoma Allografts.

OBJECTIVE: Dexamethasone (DEXA) has been widely used in the management of peritumoral brain edema. DEXA, however, has many systemic side effects and can interact negatively with glioma therapy. Progesterone (PROG), however, is a well-tolerated and readily accessible anti-inflammatory and antiedema agent, with potent neuroprotective properties. We investigated whether PROG could serve as a viable alternative to DEXA in the management of peritumoral brain edema. METHODS: We used an orthotopic C6 glioblastoma model with male Sprague-Dawley rats. Tumor grafts were allowed to grow for 14 days before drug treatment with DEXA 1 mg/kg, PROG 10 mg/kg, or PROG 20 mg/kg for 5 consecutive days. The overall animal survival and neurologic function were evaluated. Mechanistic studies on blood-brain barrier permeability and angiogenic responses were performed on the ex vivo tumor grafts. RESULTS: We found that all drug treatments prolonged overall survival to different extents. PROG 10 mg led to significantly longer survival and better preservation of neurologic function and body weight. The blood-brain barrier permeability was better preserved with PROG 10 mg than with DEXA, possibly through downregulation of matrix metalloproteinase-9 and aquaporin-4 expression. Antiangiogenic responses were also observed in the PROG group. CONCLUSIONS: The present proof-of-concept pilot study has provided novel information on the use of PROG as a corticosteroid-sparing agent in brain tumor management. Further translational and clinical studies are warranted.

Targeting of cytosolic phospholipase A2α impedes cell cycle re-entry of quiescent prostate cancer cells.

Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A2α (cPLA2α) is an enzyme that hydrolyzes membrane glycerophospholipids to release arachidonic acid and lysophospholipids that are implicated in cancer cell proliferation. The aim of this study was to determine the role of cPLA2α in cell cycle re-entry of quiescent prostate cancer cells. When PC-3 and LNCaP cells were rendered to a quiescent state, the active form of cPLA2α with a phosphorylation at Ser505 was lower compared to their proliferating state. Conversely, the phospho-cPLA2α levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA2α with Efipladib upon induction of cell cycle re-entry inhibited the re-entry process, as manifested by refrained DNA synthesis, persistent high proportion of cells in G0/G1 and low percentage of cells in S and G2/M phases, together with a stagnant recovery of Ki-67 expression. Simultaneously, Efipladib prohibited the emergence of Skp2 while maintained p27 at a high level in the nuclear compartment during cell cycle re-entry. Inhibition of cPLA2α also prevented an accumulation of cyclin D1/CDK4, cyclin E/CDK2, phospho-pRb, pre-replicative complex proteins CDC6, MCM7, ORC6 and DNA synthesis-related protein PCNA during induction of cell cycle re-entry. Moreover, a pre-treatment of the prostate cancer cells with Efipladib during induction of cell cycle re-entry subsequently compromised their tumorigenic capacity in vivo. Hence, cPLA2α plays an important role in cell cycle re-entry by quiescent prostate cancer cells.