pep005 and Carcinoma--Squamous-Cell

Although surgical intervention remains the standard of care for nonmelanoma skin cancer, other treatment modalities have been studied and used. Nonsurgical treatment methods include cryotherapy, topical medications, photodynamic therapy, radiation therapy, Hedgehog pathway inhibitors, programmed cell death protein 1 inhibitors, and active nonintervention. Despite the favorable efficacy of surgical treatment methods, many factors, including but not limited to patient age, preference, and severity of disease, must be taken into consideration when choosing the most appropriate, patient-centered treatment approach.

Topics: Administration, Cutaneous; Anilides; Antineoplastic Agents; Antineoplastic Agents, Immunological; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cryosurgery; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Photochemotherapy; Programmed Cell Death 1 Receptor; Pyridines; Radiotherapy; Skin Neoplasms; Watchful Waiting

Chemoprevention of nonmelanoma skin cancer should be considered in patients likely to develop numerous, invasive, or metastatic nonmelanoma skin cancers. This article reviews the various topical and systemic substances studied as chemopreventive agents.

Topics: Administration, Cutaneous; Administration, Oral; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chemoprevention; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Niacinamide; Photochemotherapy; Retinoids; Skin Neoplasms

To present a brief review of periorbital cutaneous tumorogenesis, highlighting the steps which might be amenable to topical treatments and then discuss the use of topical agents in the management of periorbital skin malignancy.. A rapid expansion in the understanding of the pathogenesis of melanoma and nonmelanoma skin cancer has allowed the development of a number of topical agents targeting specific tumor-forming processes. Topical agents have been shown to be effective in the management of periorbital skin malignancy.. 5-Fluorouracil and imiquimod have established roles in the management of periorbital skin malignancy. Newer agents such as ingenol mebutate, tazarotene, and diclofenac gel probably have evolving roles that require further research but show promise.

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Fluorouracil; Humans; Imiquimod; Mitomycin; Orbital Neoplasms; Skin Neoplasms

Actinic keratoses (AKs) are common skin lesions association with increased exposure to ultraviolet radiation; these lesions have the potential to transform into squamous cell carcinomas (SCCs).1.

Topics: Aminolevulinic Acid; Carcinoma, Squamous Cell; Clinical Trials as Topic; Diterpenes; Fluorouracil; Humans; Imiquimod; Incidence; Keratosis, Actinic; Patient Preference; Photochemotherapy; Photosensitizing Agents; Risk Assessment; Skin Neoplasms; Treatment Outcome

Ingenol mebutate (IM) is a novel drug currently only FDA-approved for the treatment of actinic keratosis. However, it has been extensively used off-label to treat multiple other skin disorders. In recent years, literature has emerged providing evidence for IM’s use as treatment for dermatologic disorders beyond actinic keratosis, including squamous cell carcinoma in situ. Here, we report a case series in which topical 0.05% ingenol mebutate was used to treat squamous cell carcinoma in situ, with five of six patients demonstrating successful results. J Drugs Dermatol. 2021;20(2):169-171. doi:10.36849/JDD.5602.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Carcinoma in Situ; Carcinoma, Squamous Cell; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Off-Label Use; Protein Kinase Inhibitors; Skin; Skin Neoplasms; Treatment Outcome

Topics: Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Retrospective Studies; United States; United States Food and Drug Administration

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Diterpenes; Humans; Keratosis, Actinic; Male; Scalp; Skin Neoplasms

Topics: Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Skin Neoplasms

Ingenol mebutate is an actinic keratosis treatment, which has a dual action mechanism. It allows a rapid cellular death and a severe inflammation.. We report the case of a 75 years old patient with a rapidly growing tumor 5 weeks after application of ingenol mebutate on typical actinic keratosis. Histological analysis after surgical excision showed an invasive squamous cell carcinoma (SCC); with aggressiveness signs: perineural infiltration and vascular permeation.. Ingenol mebutate's common side effects are benign and regressive within 2 to 4 weeks. There are erythema, edema, crusts, and ulcerations/erosions. Squamous cell carcinoma development was rarely reported. We have tried to collect other cases in the literature and in pharmacovigilance centres: three similar cases were recently published in the literature, 21 cases were notified to the European Medicines Agency and we asked French pharmacovigilance centres and found 5 cases of SCC after ingenol mebutate application. The role of the molecule in SCC development is currently unknown. Induced inflammation could take part in the development of these tumors. We compare this case with other situations of inflammation, such skin graft donor site or surgical incision, complicated of rapidly growing SCC. Our case, literature's and pharmacovigilance's cases encourage us to follow ingenol mebutate's side effects. Careful follow-up and registration of such cases are important to gain further insight on this topic.

Topics: Administration, Cutaneous; Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Disease Progression; Diterpenes; Humans; Inflammation; Irritants; Keratosis, Actinic; Male; Neoplasm Invasiveness; Skin Neoplasms

Actinic keratosis (AK) is an in situ squamous cell carcinoma which is mostly found on sun-damaged skin, and it is prevalent among Caucasians. However, there is a lack of research on evaluating the treatment efficacy of ingenol mebutate (IM) on AK in Asians. This study was intended to analyze the treatment outcomes of IM on AK in Korean patients with regards to clinical, dermoscopic and histopathological aspects. A prospective study on 46 Korean patients who were diagnosed with AK and treated with IM was conducted. Clinically, 80% (24/30) of the patients showed an improvement at 8 weeks. Twenty out of the 30 (66.7%) patients were found to have achieved histopathological clearance. All local skin responses had disappeared at T4 in all patients. Patients with Fitzpatrick skin type III were proven to exhibit better treatment outcomes, both clinically (P = 0.001) and histopathologically (P = 0.001), than those with Fitzpatrick skin type IV. The clinical and histopathological clearance rate of AK with IM in Korean patients was 80% and 66.7%, respectively. The patients with Fitzpatrick skin type IV showed a tendency to have residual AK, histopathologically after treatment with IM. In conclusion, IM could be an effective and safe treatment option on AK in Korean patients. In addition, it would be helpful to carry out a cautious check-up when treating AK with IM in patients with a darker skin color.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Squamous Cell; Dermoscopy; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Prospective Studies; Republic of Korea; Skin; Skin Neoplasms; Treatment Outcome

Topics: Aged, 80 and over; Carcinoma, Squamous Cell; Diterpenes; Granulation Tissue; Humans; Male; Scalp; Skin Diseases; Skin Neoplasms; Treatment Outcome

Squamous cell carcinoma of the skin is the second most common cutaneous malignancy. Despite various available treatment methods and advances in noninvasive diagnostic techniques, the incidence of metastatic cutaneous squamous cell carcinoma is rising. Deficiency in effective preventive or treatment methods of transformed keratinocytes leads to necessity of searching for new anticancer agents. The present study aims to evaluate the possibility of using wool hydrolysates as such agents. Commercially available compounds such as 5-fluorouracil, ingenol mebutate, diclofenac sodium salt were also used in this study. The process of wool degradation was based on chemical pre-activation and enzymatic digestion of wool. The effect of mentioned compounds on cell viability of squamous carcinoma cell line and healthy keratinocytes was evaluated. The obtained data show a significantly stronger effect of selected wool hydrolysates compared to commercial compounds (p<0.05) on viability of cells. The wool hydrolysates decreased squamous cell carcinoma cells viability by up to 67% comparing to untreated cells. These results indicate bioactive properties of wool hydrolysates, which affect the viability of squamous carcinoma cells and decrease their number. We hypothesize that these agents may be used topically for treatment of transformed keratinocytes in actinic keratosis and invasive squamous skin cancer in humans.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Diclofenac; Diterpenes; Fluorouracil; Humans; Keratinocytes; Protein Hydrolysates; Skin Neoplasms; Wool

Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effe

Topics: Administration, Cutaneous; Animals; Carcinoma, Squamous Cell; Denmark; Dermatologic Agents; Diterpenes; Glucocorticoids; Humans; Keratosis, Actinic; Mice; Pain; Pruritus; Skin Neoplasms; Treatment Outcome; Ultraviolet Rays

Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by widespread human papillomavirus (HPV) associated lesions and an increase susceptibility to cutaneous malignancies. A host of medications traditionally used to treat warty lesions have been used with variable results and limited success. To our knowledge, we describe the first reported case of a patient with Imiquimod resistant EV successfully treated with topical ingenol mebutate (Picato).. A patient with a 5 year history of EV failed to respond to a 6 week course of 5% imiquimod on the forehead and was subsequently treated with a 3 day course of 0.015% Picato gel which resulted in significant clinical improvement. A one month follow-up examination showed no reoccurrence of the lesions with the patient reporting continued satisfaction of the outcome.. Our case provides insight into the potential use of ingenol mebutate for EV patients unresponsive to traditional medical treatments.

Topics: Acitretin; Adult; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Drug Resistance; Epidermodysplasia Verruciformis; Female; Gels; Humans; Imiquimod; Keratolytic Agents; Rare Diseases; Skin Neoplasms; Treatment Outcome; Tretinoin

We present the case of a 73-year-old male patient who had received a first renal transplant at 36 years and a second one at the age of 55 years. He is currently under immunosuppression with everolimus 2.5 mg/day and prednisone 5 mg/day. The patient presented with multiple actinic keratoses on both cheeks and the forehead and received treatment by ingenol mebutate 150 µg/g gel daily on 3 consecutive days on his right cheek and methyl aminolevulinate (MAL) photodynamic therapy activated by daylight (MAL-dPDT) on the forehead and the left cheek. MAL-dPDT treatment proved a feasible, repeatable, physician-directed method of treating field cancerization with limited morbidity for a period of 6 days. Treatment with ingenol mebutate gel was a feasible, possibly self-directed method of treating field cancerization with limited morbidity for 10 days in this immunosuppressed patient. Both treatments showed similar efficacy. At the time of treatment, the MAL daylight PDT ran at 3 times the cost of ingenol mebutate gel.

Topics: Aged; Aminolevulinic Acid; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Face; Humans; Keratosis, Actinic; Kidney Transplantation; Male; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms; Transplant Recipients

Patients suffering from chronic lymphocytic leukemia often develop actinic keratosis (AK) and squamous cell carcinoma in sun-exposed areas. In these particular patients, who have a suboptimal immune function, AK treatment can be particularly challenging. We report the case of a patient who failed to respond to most AK treatments, including 5-FU, imiquimod and photodynamic therapy, but responded to ingenol mebutate. We started with 3 applications of 150 μg/g (registered treatment of the scalp) and also 2 applications of 500 μg/g (registered in for trunk and extremities). Both treatments were well tolerated, but only the latter led to significant clinical success. This suggests that 500 μg/g of ingenol mebutate may represent an interesting therapeutic option in patients with mild immunosuppression.

Topics: Aged; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Scalp; Skin Neoplasms

The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement.. Hairless mice (n=150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days after each IngMeb treatment.. IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR+IngMeb day 189; p=0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR+IngMeb 1.8; p<0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2)=0.257, p<0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR+CP+IngMeb 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001).. Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans.

Topics: Animals; Carcinogenesis; Carcinoma, Squamous Cell; Diterpenes; Female; Mice; Mice, Hairless; Pigmentation; Skin; Skin Neoplasms; Ultraviolet Rays

Actinic keratoses (AKs) are defined as cutaneous areas of atypical squamous transformation that are regarded as an early step in the continuum of alterations leading from normal skin to invasive and metastatic squamous cell carcinoma (SCC). AKs are classified as precancerous lesions by some authors and in situ SCC by others. The rate of evolution of a given AK to an invasive SCC has been estimated as 0·075-0·096% per lesion per year. These rates are similar to those estimated for gynaecological intraepithelial neoplasia. We describe two cases of SCC with rapid onset that developed after the application of ingenol mebutate gel for the treatment of AKs.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Drug Eruptions; Facial Dermatoses; Facial Neoplasms; Female; Head and Neck Neoplasms; Humans; Keratosis, Actinic; Skin Neoplasms

Actinic keratoses (AKs) are premalignant skin lesions caused by cumulative ultraviolet-light exposure that may progress to invasive squamous cell carcinoma (SCC). As the clinical presentation of AKs varies widely, only a histopathologic analysis of a biopsied sample can eliminate or confirm a diagnosis of invasive SCC. Reducing the burden of AK with a combination of lesion-directed and field-directed treatments may help to identify persistent, suspicious lesions that require further evaluation. We present 10 cases of SCC that were identified and histologically confirmed in 7 patients after complete or substantial clearance of AKs by sequential treatment of sun-damaged skin with cryosurgery and ingenol mebutate.

Topics: Aged; Antineoplastic Agents; Biopsy; Carcinoma, Squamous Cell; Combined Modality Therapy; Cryosurgery; Diterpenes; Facial Neoplasms; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp; Skin; Skin Neoplasms

Topics: Aminoquinolines; Carcinoma, Squamous Cell; Case Management; Clinical Trials as Topic; Cryosurgery; Diagnosis, Differential; Diclofenac; Disease Management; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Italy; Keratosis, Actinic; Laser Therapy; Neoplasms, Radiation-Induced; Photochemotherapy; Practice Guidelines as Topic; Skin Neoplasms; Sunscreening Agents; United Kingdom; United States; Watchful Waiting

Ingenol mebutate has recently been approved by the Federal Drug Administration (USA) as a topical treatment for actinic keratoses. Herein, we describe the efficacy of ingenol mebutate for the topical treatment of squamous cell carcinoma (SCC) using a wild-type mouse model (SKH1) and the UV-induced mouse SCC cell line, T7. Daily treatment for 2 days with 0.25 % ingenol mebutate gel produced a cure rate of 70 %, with 0 % for placebo gel. Electron microscopy revealed swelling of cancer cell mitochondria within 1 h, with disruption of the inner mitochondrial membranes evident at 6 h post treatment. Primary necrosis of cancer cells was clearly evident by 24 h. Treatment was associated with local haemorrhage and a prodigious neutrophil infiltrate, with anti-T7 antibodies also detected. This is the first report of the successful treatment of SCC tumours with ingenol mebutate gel in wild-type mice, and supports the view that ingenol mebutate induces primary necrosis and activates the immune system.

Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Diterpenes; Female; Gels; Male; Mice; Mice, Hairless; Microscopy, Electron; Mitochondria; Mitochondrial Swelling; Necrosis; Neutrophil Infiltration; Skin Neoplasms; Time Factors

Topics: Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Ultraviolet Rays

Skin cancer is the most prevalent cancer worldwide and is primarily caused by chronic UV exposure. Here, we describe the topical field-directed treatment of SKH1/hr mice with UVB-damaged skin with ingenol mebutate, a new topical drug shown to be effective for the treatment of actinic keratosis (AK). Application of 0.05% ingenol mebutate gel to photo-damaged skin resulted in a ≈70% reduction in the number of skin lesions that subsequently emerged compared with placebo treatment. Ingenol mebutate treatment also reduced the number of mutant p53 keratinocyte patches by ≈70%. The treatment resulted in epidermal cell death, acute inflammation, recruitment of neutrophils, hemorrhage, and eschar formation, all of which resolved over several weeks. Ingenol mebutate field-directed treatment might thus find utility in the removal of subclinical precancerous cells from UV-damaged skin. Field-directed treatment may be particularly suitable for patients who have AKs surrounded by UV-damaged skin.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Keratinocytes; Keratosis, Actinic; Male; Mice; Mice, Hairless; Mutation; Neoplasms, Radiation-Induced; Precancerous Conditions; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

We investigated the proposed necrotic mechanism of ingenol mebutate, a natural compound with anti-cancer properties in human keratinocytes, the human squamous cell carcinoma cell line HSC-5, and HeLa cervix carcinoma cells. Topical application of a clinical dose of ingenol mebutate 0.05% (1.15 mM) gel to human reconstituted full-thickness skin equivalents strongly reduced epidermal, but not dermal viability. Ingenol mebutate showed cytotoxic potency between 200-300 M on normal and cancer cells. When keratinocytes were induced to differentiate, they became significantly less sensitive to ingenol mebutate and half-maximal induction of cell death required more than 300 M ingenol mebutate. Cytotoxic concentrations of ingenol mebutate caused rupture of the mitochondrial network within minutes paralleled by cytosolic calcium release in all cells. Subsequently, plasma membrane integrity was lost as seen by propidium uptake into the cells. This was in sharp contrast to lysis of cells with low concentrations of the detergent Triton X-100 that permeabilized the plasma membrane within minutes without affecting organelle morphology. Buffering of intracellular calcium and inhibition of the mitochondrial permeability transition pore reduced the cytotoxic effect of ingenol mebutate in cancer cells, but not in normal keratinocytes. However, these inhibitors could not prevent cell death subsequent to prolonged incubation. Our findings reveal that ingenol mebutate does not mediate cytotoxicity by a simple lytic, necrotic mechanism, but activates distinct processes involving multiple cell organelles in a cell-type and differentiation-dependent manner. These data improve our understanding of ingenol mebutate-target cell interactions and offer new insights relevant to the removal of aberrant cells in human skin.

Topics: Antineoplastic Agents, Phytogenic; Calcium; Carcinoma, Squamous Cell; Cell Differentiation; Cell Membrane; Cell Survival; Detergents; Diterpenes; HeLa Cells; Humans; Keratinocytes; L-Lactate Dehydrogenase; Mitochondria; Necrosis; Octoxynol; Skin

Topics: Aminoquinolines; Antineoplastic Agents; Carcinoma, Squamous Cell; Cryotherapy; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Skin Neoplasms

Ingenol-3-angelate (Ing3A), extracted from Euphorbia peplus, is currently in clinical trials for eradicating basal cell carcinoma, actinic keratosis, and squamous cell carcinoma (SCC) in situ by topical application. Although structurally related to phorbol esters and a protein kinase C activator, topical Ing3A, but not phorbol 12-myristate 13-acetate (PMA), inhibited the growth of subcutaneous tumors derived from PAM212 (mouse SCC) and B16 (mouse melanoma). Ing3A and PMA both induced acute neutrophilic inflammation on mouse skin, but only Ing3A caused subcutaneous hemorrhage and vascular damage. Both Ing3A and PMA activated extracellular signal-regulated kinase 1/2 (ERK1/2) in epidermis, but Ing3A also activated ERK1/2 in skin dermal fibroblasts and endothelial cells. Pretreatment with topical cyclosporin A (CsA), verapamil, or XR9576, modulators of P-glycoprotein (P-gp), prevented Ing3A-induced hemorrhage but not neutrophil infiltration. CsA also impaired the anticancer activity of Ing3A, whereas the anti-inflammatory dexamethasone did not. Ing3A, but not PMA, blocked photoaffinity labeling of human P-gp with [(125)I]iodoaryazidoprazosin and inhibited P-gp-mediated drug resistance to HCT-15 cells. The intracellular levels of Ing3A were significantly lower in P-gp-expressing cells, and treatment with XR9576 increased the levels to those of cells that do not express P-gp, showing that Ing3A binds to and is transported by P-gp. Taken together, our results suggest that P-gp-mediated absorptive transport, dermal penetration, and vascular damage contribute to the anticancer activity of Ing3A in vivo.

Topics: Administration, Topical; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Squamous Cell; Cell Line, Tumor; Diterpenes; Drug Eruptions; Enzyme Activation; Humans; Keratinocytes; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Protein Binding; Protein Kinase C; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate