Analysis of apoptosis‐associated molecules Erythroid differentiation regulator 1, bcl‐2 and p53 in actinic keratosis after treatment with ingenol mebutate

Abstract

Actinic keratosis (AK) is the most common cutaneous premalignant neoplasm precursor of malignant skin tumors. The aberrant apoptotic pathway is thought to be associated with pathogenesis of AK. Ingenol mebutate has been shown to be effective and safe for treatment of AK. However, the effect of ingenol mebutate on apoptosis-related molecules using human skin samples has not been studied well. Erythroid differentiation regulator 1 (Erdr1) was recently reported to play a crucial role in malignant skin cancers like malignant melanoma. The role of Erdr1 in premalignant actinic keratosis (AK) has not been explored. The purpose of this study was to investigate whether the expression of apoptosis-associated molecules such as Erdr1, p53 and bcl-2 was affected by the treatment of ingenol mebutate in AK. Nine patients with AK underwent skin biopsy at baseline and 8 weeks after treatment with ingenol mebutate for immunohistochemical evaluation with Erdr1, p53 and bcl-2. In addition, skin samples from five control subjects were retrieved. Upregulation of Erdr1 and a significant decrease in expression of p53 and bcl-2 were observed after treatment with ingenol mebutate. Ingenol mebutate treatment for AK resulted in the modulation of apoptosis-associated molecules with an increase in the expression of Erdr1 and a decrease in the expression of p53 and bcl-2.

Ingenol mebutate‐mediated reduction in p53‐positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses

“…16,17,[20][21][22][23] It is commonly believed that chronic UV radiation exposure represents the crucial risk factor for NMSC, 1 being responsible of several mutations on p53 suppressor gene, typically involved in the apoptosis of DNA-damaged keratinocytes. 16,17,[20][21][22][23] It is commonly believed that chronic UV radiation exposure represents the crucial risk factor for NMSC, 1 being responsible of several mutations on p53 suppressor gene, typically involved in the apoptosis of DNA-damaged keratinocytes.…”

“…21 In order to clarify ingenol mebutate mechanism of action in sun-damaged skin, recent investigations in mouse models suggested that this drug is able to destroy specifically skin-mutated p53 + keratinocytes, inducing a significant histologically reduction in mutant p53 patches. 21 In order to clarify ingenol mebutate mechanism of action in sun-damaged skin, recent investigations in mouse models suggested that this drug is able to destroy specifically skin-mutated p53 + keratinocytes, inducing a significant histologically reduction in mutant p53 patches.…”

“…21 In order to clarify ingenol mebutate mechanism of action in sun-damaged skin, recent investigations in mouse models suggested that this drug is able to destroy specifically skin-mutated p53 + keratinocytes, inducing a significant histologically reduction in mutant p53 patches. 21 Furthermore, we reported for the first time a strong, direct correlation between the reduction in the number of p53 + keratinocytes and clinical reduction in AK at 2 months from treatment and at 6-month follow-up: in patients with p53 + keratinocyte reduction at 2 months, we observed AK reduction at the same time point, while in patients without significant change in p53 + keratinocytes between pre-and post-treatment, ingenol mebutate was not clinically effective and we recorded SD or even new AK lesions. First off we showed, even though in a small number of patients, the elevated presence of p53 + keratinocytes in untreated skin CF samples, similar to those observed in invasive SCC.…”

“…In the last years, ingenol mebutate has emerged as an effective molecule for AK topical treatment, belonging to the 'field-therapy' or 'field-directed' drugs, which represent the better therapeutic choice for patients with multiple AKs, as compared to 'lesion-directed' treatments. 16,17,[20][21][22][23] It is commonly believed that chronic UV radiation exposure represents the crucial risk factor for NMSC, 1 being responsible of several mutations on p53 suppressor gene, typically involved in the apoptosis of DNA-damaged keratinocytes. [4][5][6][7] UVdamaged keratinocytes, with mutated p53, replicate and form the so-called 'p53 patches' in skin, 4,8,9 which might develop in AK, 7,10 and later on in NMSC.…”

“…More recently, it has been reported that ingenol mebutate is able to modulate the three apoptosis-related molecules, inducing erythroid differentiation regulator 1 (Erd-1) increase and bcl-2/ p53 decrease in examined AK lesions. 21 In order to clarify ingenol mebutate mechanism of action in sun-damaged skin, recent investigations in mouse models suggested that this drug is able to destroy specifically skin-mutated p53 + keratinocytes, inducing a significant histologically reduction in mutant p53 patches. 15 Taking advantage of that study, we decided to analyse p53 expression in keratinocytes from skin CF near AK lesions, before and after treatment with ingenol mebutate, in order to elucidate whether the compound was able to significantly reduce perilesional p53 + keratinocytes at 2 months from treatment compared to baseline and whether these data might affect AK recurrence.…”