Abstract
Glioblastomas are high-grade, malignant CNS neoplasms that are nearly always fatal within 12 months of diagnosis. Immunotherapy using proinflammatory cytokines such as IL-2 or IL-12 may prolong survival with glioblastoma. Thymosin-alpha1 (Talpha1) is a thymic hormone and immunemodulator that increase IL-2 production and T-cell proliferation. We examined potential therapeutic effects of Talpha1 in experimental in vivo glioblastoma, and characterized Talpha1's anti-tumor effects in vitro. Rar 9L cells (10(4)) were implanted into the right frontal lobe of adult Long Evans rats that were subsequently treated with vehicle, BCNU, Talpha1, or Talpha1+BCNU from postoperative day 6. Talpha1+BCNU significantly lowered tumor burdens, and increased cure rates. In vitro experiments demonstrated that Talpha1 had no direct effect on viability or mitochondrial function, and instead, it increased expression of pro-apoptosis genes, including FasL, FasR and TNFalpha-R1 (65.89%, 44.08%, and 22.18%, resp.), and increased 9L cell sensitivity to oxidative stress. Moreover, Talpha1 enhanced 9L cell sensitivity to both Granzyme B- and BCNU-mediated killing. The findings suggest that Talpha1 enhances BCNUmediated eradication of glioblastoma in vivo, and that Talpha1 mediates its effects by activating pro-apoptosis mechanisms, rendering neoplastic cells more sensitive to oxidative stress and immune-mediated killing by Granzyme B and chemotherapeutic agents.