Journal article
Antitumor Activity of 3-Ingenyl Angelate Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death
Cancer Research, Vol.34(8), pp.2833-2839
2004
Abstract
Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodessication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 μg) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; n = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; n = >4 tumors/group) previously established (5-10 mm3) on C57BL/6 or Foxn1nu mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD90 for PEP005 for a panel of tumor cell lines was 180-220 μm. Electron microscopy showed that treatment with PEP005 both in vitro (230 μm) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. 51Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 μm) treatment of tumor cells in vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.
Details
- Title
- Antitumor Activity of 3-Ingenyl Angelate Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death
- Authors
- Steven Ogbourne (Author) - Queensland Institute of Medical ResearchA Suhrbier (Author) - Queensland Institute of Medical ResearchB Jones (Author) - Queensland Institute of Medical ResearchS J Cozzi (Author) - Queensland Institute of Medical ResearchG M Boyle (Author) - Queensland Institute of Medical ResearchM Morris (Author) - Queensland Institute of Medical ResearchD McAlpine (Author) - Queensland Institute of Medical ResearchJ Johns (Author) - Queensland Institute of Medical ResearchT M Scott (Author) - Queensland Institute of Medical ResearchK P Sutherland (Author) - Queensland Institute of Medical ResearchJ Gardner (Author) - Queensland Institute of Medical ResearchThuy T T Le (Author) - Queensland Institute of Medical ResearchA Lenarczyk (Author) - Queensland Institute of Medical ResearchJ Aylward (Author) - Peplin Biotech Ltd.P G Parsons (Author) - Queensland Institute of Medical Research
- Publication details
- Cancer Research, Vol.34(8), pp.2833-2839
- Publisher
- American Association for Cancer Research
- Date published
- 2004
- DOI
- 10.1158/0008-5472.CAN-03-2837
- ISSN
- 0008-5472
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99450144802621
- Output Type
- Journal article
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