Potential Role of Thymosin-α1 Adjuvant Therapy for Glioblastoma

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-α1 (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 (104) 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 TNFα-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.

Thymus hormones as prospective anti-inflammatory agents

“…Such a combination of features theoretically would be beneficial for viral and oncological disorder treatments. Indeed, thymosin-alpha administration has been shown to have positive effects in glioblastoma eradication [90], and hepatitis B treatment [91]. Thymopoietin stimulates immune cells in healthy humans and animals and inhibits immune responses under stress conditions, being very promising for clinical application.…”

GBM skin metastasis: a case report and review of the literature

“…Our patient also received thymalfasin (also known as thymosin-α1 or Talpha1) as part of her initial management, which has not been studied as much as interferon in the treatment of GBM. Thymalfasin is a synthetic analog of a naturally occurring hormone that circulates in the thymus and stimulates thymocyte growth and differentiation [35]. Animal studies have shown some potential benefit in combination with carmustine against GBM and glioma cells [13,36].…”

Thymosin alpha 1: Biological activities, applications and genetic engineering production

“…In DHD-K12 colorectal cancer model, combination of 5-FU, IL-2 and T␣1 could dramatically increase survival rates as well as control tumor metastasis [26]. Similarly, compared with Carmustine (BCNU) monotherapy, intraperitoneal injection of T␣1 and BCNU to adult Long Evans rats bearing glioblastoma could significantly lower the tumor burdens and increase the cure rates [73]. Since the cascades and feedback networks of immune responses, the combination of immunoactive molecules that affected different immune effector cells resulted in a stimulation of the immune response significantly stronger than that evoked by single treatments.…”