Antitumor Activity of 3-Ingenyl Angelate

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 g) 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 mm 3 ) 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 LD 90 for PEP005 for a panel of tumor cell lines was 180 -220 M. Electron microscopy showed that treatment with PEP005 both in vitro (230 M) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. 51 Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 M) 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.

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

“…In previously published studies, PEP005 displayed antiproliferative effects in several human cancer cell lines (Gillespie et al, 2004;Ogbourne et al, 2004;Hampson et al, 2005;Cozzi et al, 2006). Studies that evaluated the activity of PEP005 as a topical agent for human and mouse xenografts have shown that the predominant mechanism of cell death is necrosis (Ogbourne et al, 2004) and in some melanoma cell lines apoptosis was observed (Gillespie et al, 2004). The capacity of PEP005 to induce apoptosis was further confirmed using leukaemia cancer cells (Hampson et al, 2005).…”

“…In leukaemia cells, resistance to PEP005 was associated with the failure to express PKCd. In solid tumours, PEP005 was shown to induce necrosis in human melanoma, cervical cancer, and prostate xenografts (Ogbourne et al, 2004).…”

Evaluation of inhibitory effect and apoptosis induction of Zyzyphus Jujube on tumor cell lines, an in vitro preliminary study

“…Whether the anti proliferative activity observed for the Zyzyphus Jujube extract is due to the induction of apoptosis was examined in our study. Results of DNA fragmentation showed Zyzyphus Jujube has the ability to induce apoptosis in Jurkat cells (Ogbourne et al 2004). Previously, the anti proliferative activity in gastric tumors in nude mice has been demonstrated for CKBM, a mixture of natural herbs containing Zyzyphus Jujube.…”

“…Apoptosis is a highly regulated process that occurs as part of differentiation, proliferation and growth of normal and malignant cells and plays a critical role in tumor initiation, progression, as well as in cancer therapy (Kim et al 2002;Ogbourne et al 2004). Whether the anti proliferative activity observed for the Zyzyphus Jujube extract is due to the induction of apoptosis was examined in our study.…”

Analysis by Fluorescence Resonance Energy Transfer of the Interaction between Ligands and Protein Kinase Cδ in the Intact Cell

“…Indeed, a number of compounds targeting protein kinase C are currently at different stages of drug development. Examples include LY333531, being evaluated for diabetic retinopathy and anti-angiogenesis (1, 2), prostratin and dPP, being evaluated for AIDS chemotherapy (3,4), and bryostatin 1 and ingenol 3-angelate, being evaluated as cancer chemotherapeutic agents (5)(6)(7).…”