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Antitumor Activity of 3-Ingenyl Angelate

Plasma Membrane and Mitochondrial Disruption and Necrotic Cell Death

¹ Queensland Institute of Medical Research, Melanoma Genomics Group, Brisbane; ² Queensland Institute of Medical Research, Infectious Disease Unit, Brisbane; and ³ Peplin Biotech Ltd, Brisbane, Queensland, Australia

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 Foxn1^nu 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.

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