PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors

• Published in: Cancer biology & therapy Vol. 4; no. 5; pp. 538 - 545
• Main Authors: Yu, Ker, Lucas, Judy, Zhu, Tianmin, Zask, Arie, Gaydos, Christine, Toral-Barza, Lourdes, Gu, Jianxin, Li, Fangbiao, Chaudhary, Inder, Cai, Ping, Lotvin, Jason, Petersen, Roseann, Ruppen, Mark, Fawzi, Mahdi, Ayral-Kaloustian, Semiramis, Skotnicki, Jerauld, Mansour, Tarek, Frost, Philip, Gibbons, James
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.05.2005
• Subjects: Androstadienes - chemistry; Androstadienes - pharmacology; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Phytogenic - pharmacology; Binding; Biology; Bioscience; Calcium; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell; Cell Line, Tumor; Cycle; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; Interferon-alpha - therapeutic use; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Landes; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Nude; Molecular Structure; Molecular Weight; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Organogenesis; Paclitaxel - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Sirolimus - pharmacology; Transplantation, Heterologous; Xenograft Model Antitumor Assays
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.4.5.1660

Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in-vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, non-small cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-? (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.