Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal

• Published in: Cancer science Vol. 94; no. 1; pp. 15 - 21
• Main Authors: Tsuruo, Takashi, Naito, Mikihiko, Tomida, Akihiro, Fujita, Naoya, Mashima, Tetsuo, Sakamoto, Hiroshi, Haga, Naomi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2003; Blackwell; John Wiley & Sons, Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; 3-Phosphoinositide-Dependent Protein Kinases; AKT protein; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Biological and medical sciences; Biological Transport - drug effects; Cancer; Cancer therapies; Cell Hypoxia; Cell Nucleus - enzymology; Cell Survival; Cysteine Endopeptidases - physiology; Deoxyribonucleic acid; Detoxification; DNA; DNA topoisomerase (ATP-hydrolysing); Drug Design; Drug development; Drug resistance; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Geldanamycin; General aspects; Glycolysis; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - physiology; Humans; Hypoxia; Lactoylglutathione lyase; Lactoylglutathione Lyase - antagonists & inhibitors; Lactoylglutathione Lyase - physiology; MDR1 protein; Medical sciences; Molecular modelling; Multidrug resistance; Multienzyme Complexes - physiology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - physiology; Neoplasms - drug therapy; Neoplasms - metabolism; Oxidative Stress; P-Glycoprotein; Pharmacology. Drug treatments; Protease Inhibitors - pharmacology; Protease Inhibitors - therapeutic use; Proteasome Endopeptidase Complex; Proteasome inhibitors; Protein transport; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - physiology; Protein-tyrosine kinase; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; Signal Transduction - drug effects; Solid tumors; Starvation; Tumor cells; Tumors; Antineoplastic agent; Multicatalytic endopeptidase complex; Targeting; P Glycoprotein; Lyases; Review; Signal transduction; Gene; Multiple resistance; Carbon-sulfur lyases; Genetics; Human; Treatment resistance; Cell survival; Enzyme; Akt protein kinase; Malignant tumor; Peptidases; Treatment; Cell death; Hydrolases; Reversibility; Lactoylglutathione lyase; ABC transporter; Apoptosis
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2003.tb01345.x

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival‐signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P‐Glycoprotein (P‐gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P‐gp by small‐molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P‐gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multi‐drug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome‐mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress‐induced drug resistance. Glyoxalase I, which is often elevated in drug‐ and apoptosis‐resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug‐resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro‐apoptotic and survival (anti‐apoptotic) signals. PI3K‐Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN‐01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics. (Cancer Sci 2003; 94: 15–21)