Radiosensitization of Squamous Cell Carcinoma by the Alkylphospholipid Perifosine in Cell Culture and Xenografts

Abstract

Purpose: Combined modality treatment has improved outcome in various solid tumors. Besides classic anticancer drugs, a new generation of biological response modifiers has emerged that increases the efficacy of radiation. Here, we have investigated whether perifosine, an orally applicable, membrane-targeted alkylphospholipid, enhances the antitumor effect of radiation in vitro and in vivo. Experimental Design: Several long-term and short-term in vitro assays (clonogenic survival, sulforhodamine B cytotoxicity, apoptosis, and cell cycle analysis) were used to assess the cytotoxic effect of perifosine in combination with radiation. In vivo, the response of human KB squamous cell carcinoma xenografts was measured after treatment with perifosine, irradiation, and the combination. Radiolabeled perifosine was used to determine drug disposition in tumor and normal tissues. At various intervals after treatment, tumor specimens were collected to document histopathologic changes. Results: In vitro, perifosine reduced clonogenic survival, enhanced apoptosis, and increased cell cycle arrest after radiation. In vivo, radiation and perifosine alone induced a dose-dependent tumor growth delay. When combining multiple perifosine administrations with single or split doses of radiation, complete and sustained tumor regression was observed. Histopathologic analysis of tumor specimens revealed a prominent apoptotic response after combined treatment with radiation and perifosine. Radiation-enhanced tumor response was observed at clinically relevant plasma perifosine concentrations and accumulating drug disposition of >100 μg/g in tumor tissue. Conclusions: Perifosine enhances radiation-induced cytotoxicity, as evidenced by reduced clonogenic survival and increased apoptosis induction in vitro and by complete tumor regression in vivo. These data provide strong support for further development of this combination in clinical studies.

Perifosine: Update on a novel Akt inhibitor

“…With the combination of perifosine and TRAIL, death depended on DR4 and DR5 expression, but not Akt [51]. In mice bearing human tumors in vivo, combinations of perifosine and temozolomide [13] or radiation [54] have shown promise. In AML blasts, perifosine increased sensitivity to etoposide [15].…”

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

“…Perifosine is an oral alkylphospholipid, which interferes with the recruitment of Akt to the plasma membrane and inhibits the phosphorylation of Akt and multiple of its downstream targets including MDM2, GSK3a/b, and p70S6K (Momota et al 2005, Rahmani et al 2005, Hideshima et al 2006. Perifosine causes growth inhibition in various tumor cell lines and was also shown to sensitize tumor cells to conventional therapeutic antitumor agents and radiation (Momota et al 2005, Rahmani et al 2005, Vink et al 2006. As mTOR inhibition may result in the activation of upstream PI(3)K/Akt neuroendocrine signaling (Zitzmann et al 2010), direct Akt inhibition with perifosine could suppress this compensatory mechanism.…”

MicroRNA-27a inhibitors alone or in combination with perifosine suppress the growth of gastric cancer cells

“…pathway, and to affect multiple cell processes, including proliferation, survival and apoptosis (19,29,30). Perifosine has recently received wide attention due to its potential health beneficial effects (31).…”