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The Oncologist, Vol. 12, No. 12, 1395-1403, December 2007; doi:10.1634/theoncologist.12-12-1395
© 2007 AlphaMed Press

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The Community Oncologist

Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas

Florence Lefranca,b, Vincenzo Facchinic, Robert Kissb

aDepartment of Neurosurgery, Erasme University Hospital, Brussels, Belgium; bLaboratory of Toxicology, Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium; cUnibioscreen SA, Brussels, Belgium

Key Words. Apoptosis • Autophagy • Glioblastoma • Melanoma • Metastatic cancer • Temozolomide

Correspondence: Florence Lefranc, M.D., Ph.D., Department of Neurosurgery, Erasmus Academic Hospital, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium. Telephone: 32-474-477-192; Fax: 32-2-332-5335; e-mail: fllefran{at}ulb.ac.be

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

The therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy. Unlike apoptosis, which is a caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. The most striking evidence for proautophagic chemotherapy to overcome apoptosis resistance in cancer cells comes from the use of temozolomide, a proautophagic cytotoxic drug, which has demonstrated real therapeutic benefits in glioblastoma patients and is in clinical trials for several types of apoptosis-resistant cancers. A number of potential common targets in autophagy and apoptosis resistance pathways, that is, mammalian target of rapamycin (mTOR), phosphatidylinositol 3' kinase (PI3K), and Akt have been identified. Thus, further success in certain devastating cancers might be achieved by the combination of proautophagic drugs such as temozolomide with mTOR, PI3K, or Akt inhibitors, or with endoplasmic reticulum stress inhibitors as adjuvant chemotherapies.






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