Abstract
Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1α and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1α and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR- 042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.
Keywords: Fusicoccin, Hypoxia-targeting agent, Tumor stem cell, Akt, HIF-1, Pancreatic cancer, Gemcitabine, Combination therapy, Xenograft, Cotylenin, MIAPaCa-2 cells, derivative.
Anti-Cancer Agents in Medicinal Chemistry
Title:A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts
Volume: 12 Issue: 7
Author(s): Koshi Kawakami, Miho Hattori, Takatsugu Inoue, Yuriko Maruyama, Junko Ohkanda, Nobuo Kato, Miki Tongu, Takaya Yamada, Miho Akimoto, Keizo Takenaga, Takeshi Sassa, Junji Suzumiy and Yoshio Honma
Affiliation:
Keywords: Fusicoccin, Hypoxia-targeting agent, Tumor stem cell, Akt, HIF-1, Pancreatic cancer, Gemcitabine, Combination therapy, Xenograft, Cotylenin, MIAPaCa-2 cells, derivative.
Abstract: Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1α and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1α and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR- 042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.
Export Options
About this article
Cite this article as:
Kawakami Koshi, Hattori Miho, Inoue Takatsugu, Maruyama Yuriko, Ohkanda Junko, Kato Nobuo, Tongu Miki, Yamada Takaya, Akimoto Miho, Takenaga Keizo, Sassa Takeshi, Suzumiy Junji and Honma Yoshio, A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts, Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (7) . https://dx.doi.org/10.2174/187152012802650264
DOI https://dx.doi.org/10.2174/187152012802650264 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Acute Lymphoblastic Leukemia and Regulatory T cells: Biomarkers and Immunopathogenesis
Current Immunology Reviews (Discontinued) Genome-wide Analysis of Myelodysplastic Syndromes
Current Pharmaceutical Design Some Peculiar Effects of NO-Synthase Inhibition on the Structure and Function of Cardiovascular System
Current Pharmaceutical Biotechnology Dexrazoxane for the Prevention of Cardiac Toxicity and Treatment of Extravasation Injury from the Anthracycline Antibiotics
Current Pharmaceutical Biotechnology Trends in the Exploration of Anticancer Targets and Strategies in Enhancing the Efficacy of Drug Targeting
Current Molecular Pharmacology Genetic Polymorphisms of Drug Metabolising Enzymes and Drug Transporters in Relation to Cancer Risk
Current Cancer Therapy Reviews Central Nervous System Abnormalities in Fibromyalgia and Chronic Fatigue Syndrome: New Concepts in Treatment
Current Pharmaceutical Design Novel Systemic Drugs for Cutaneous T-Cell Lymphoma
Recent Patents on Anti-Cancer Drug Discovery Chromosomal Abnormalities, Cancer and Mouse Models The Critical Role of Translocation-Associated Genes in Human Cancer
Current Genomics In Vivo Optical Imaging in Gene & Cell Therapy
Current Gene Therapy Molecular Imaging of Therapeutic Potential of Reporter Probes
Current Drug Targets Molecular Advances Toward the Understanding of the Patho-Biology of Idiopathic Myelofibrosis
Current Immunology Reviews (Discontinued) Apoptosis Induction by Erucylphosphohomocholine via the 18 kDa Mitochondrial Translocator Protein: Implications for Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Huntingtons Disease: New Frontiers for Molecular and Cell Therapy
Current Drug Targets Glycosidated Phospholipids – a Promising Group of Anti-Tumour Lipids
Anti-Cancer Agents in Medicinal Chemistry SHP-2 Regulates Growth Factor Dependent Vascular Signalling and Function
Mini-Reviews in Medicinal Chemistry Foamy Virus Vectors: An Awaited Alternative to Gammaretro- and Lentiviral Vectors
Current Gene Therapy Dietary Phytochemicals in Chemoprevention of Cancer: An Update
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) The Shape of the Messenger: Using Protein Structure Information to Design Novel Cytokine-based Therapeutics
Current Pharmaceutical Design The Genetic Landscapes of Inflammation-Driven Gastrointestinal Tract Cancers
Current Pharmaceutical Design