Metastatic melanoma is the most aggressive skin cancer. Recently, phenotypically distinct subpopulations of tumor cells were identified. Among them, ABCB5-expressing cells were proposed to display an enhanced tumorigenicity with stem cell-like properties. In addition, ABCB5+ cells are thought to participate to chemoresistance through a potential efflux function of ABCB5. Nevertheless, the fate of these cells upon drugs that are used in melanoma chemotherapy remains to be clarified. Here we explored the effect of anti-melanoma treatments on the ABCB5-expressing cells. Using a melanoma xenograft model (WM266-4), we observed in vivo that ABCB5-expressing cells are enriched after a temozolomide treatment that induces a significant tumor regression. These results were further confirmed in a preliminary study conducted on clinical samples from patients that received dacarbazine. In vitro, we showed that ABCB5-expressing cells selectively survive when exposed to dacarbazine, the reference treatment of metastatic melanoma, but also to vemurafenib, a new inhibitor of the mutated kinase V600E BRAF and other various chemotherapeutic drugs. Our results show that anti-melanoma chemotherapy might participate to the chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB5. This is of particular importance in understanding the relapses observed after anti-melanoma treatments and reinforces the interest of ABCB5 and ABCB5-expressing cells as potential therapeutic targets in melanoma.

Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and carbohydrates. PPAR␥ activity increases insulin sensitivity and adipocyte differentiation at the expense of adipogenesis and weight gain. The goal of this study was to 1) clone the promoter of the human adipocyte fatty acid binding protein (aP2) gene, namely fatty acid-binding protein-4, 2) characterize its pharmacological regulation, and 3) determine its putative predictability for adipogenesis. Among the selected PPAR agonists, rosiglitazone and pioglitazone displayed the highest maximal efficacy (E max ) on reporter-gene assays in COS-7 cells cotransfected by either a galactosidase 4-response elementbased or a human aP2 promoter-based Luc reporter vector, along with either chimeric or full-length human PPAR expression plas- -0072), and indomethacin behaved as partial agonists relative to pioglitazone in full-length human aP2-PPAR␥2. Beyond their partial PPAR␥ agonist properties, these compounds elicited a lower maximal up-regulation of mouse aP2 mRNA in 3T3-L1 adipocytes as compared with pioglitazone; these properties paralleled a time-dependent increase in neutral lipids. By contrast, the selective PPAR␣ agonist 2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid (BM-17.0744) neither stimulated the human aP2-PPAR␣ promoter reporter-gene assay, thus demonstrating a specific interaction between PPAR␥ and the aP2 promoter, nor affected lipogenesis in 3T3-L1 cells. Altogether, these data characterized a functional promoter of the human aP2 gene; its in vitro pharmacological regulation in PPAR␥-mediated reporter-gene assay may represent an interesting complement or an alternative to time-consuming procedures aiming at discriminating PPAR ligands with low lipogenic properties.Metabolic syndrome is characterized by the clustering of at least three risk factors among hypertension, certain types of dyslipidemia, impaired glucose tolerance and type II diabetes, and obesity. These metabolic abnormalities lead to atherosclerosis and related complications (Haffner and Taegtmeyer, 2003). The control of lipid and carbohydrate metabolism, including physiologic and pharmacological treatments, represents a valid rationale to reduce cardiovascular diseases in patients with metabolic syndrome (Beckman et al., 2003;Wilson and Grundy, 2003).PPARs are a subclass of the nuclear receptor superfamily acting as ligand-dependent transcription factors (Kersten et al., 2000). Three subtypes were identified; the ␣ isoform is the primary subtype expressed in liver, but also in heart and kidney, and acts as a major regulator of metabolism of fats, catabolism of fatty acids, and synthesis and catabolism of lipoproteins (Barbier et al., 2002). PPAR␣ is also involved in Parts of this work were presented as a poster at the 74th Congress of the European Atherosclerosis Society (April 17-20, 2004, Seville, Spain).Article, publication date, and citation information can be found at

The Amaryllidaceous alkaloids pancratistatin and narciclasine are known to exert marginal antitumor properties but associated with toxicities. Despite extensive investigations, pancratistatin or analogues did not succeed to provide sufficient therapeutic benefit although a new pro-drug strategy was applied recently to narciclasine. We decided to undertake a chemistry program aimed at modifying the skeleton of this attractive pharmacophore in order to improve its therapeutic application. At first sight, literature survey suggests that any change in the structure would lead to a loss of activity but a careful examination of published data indicated that position −1 of the molecule may be of potential interest although poorly investigated. We report here the synthesis of a series of 39 novel derivatives of 1-aminopancratistatin by chemical modification of the naturally available narciclasine extracted from Narcissus bulbs. These new compounds present improved pharmaceutical properties such as higher aqueous solubility (from 300 µg/ml for narciclasine up to 2000 µg/ml) without loss of stability tested on human and murine microsomal assays (70-90% stability after 1h incubation). A sub-set of these novel derivatives demonstrated a drastic increase of the cytotoxic activity reaching nM range tested on a panel of 8 different cell lines. The higher antiproliferative activity translates towards the induction of stronger pro-apoptotic signals evidenced with Annexin V, caspase 3/7 and JC-1 assay. Besides the previously described inhibition of protein synthesis, our studies originally demonstrated that part of the mechanism of action involves inhibition of DNA synthesis as well. The contribution of these two pharmacological properties elaborates a SAR (structure - activity relationship) and segregates our new pancrastistatin derivatives into different categories depending on their ability to inhibit protein synthesis, DNA synthesis or both. Based on their differential in vitro activity profile, the compounds were selected for evaluation of their in vivo antitumor properties on murine and xenografted models. As a major result F 98604 (dimethylaminomethyl benzamide derivative of pancratistatin) exhibited significant and reproducible activity on the murine B16 sc and human A375 melanoma models in terms of tumor growth inhibition as well as increased therapeutic index. The present SAR suggests that modification of the natural pancratistatin or narciclasine pharmacophore at the position −1 open new perspectives as potential anticancer agents with novel pharmacological profiles. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5461.

Background This study evaluated the efficacy, safety, and acceptability of a new ferrous sulfate oral solution (Tardyferon® 20 mg/mL) in young children with mild or moderate iron deficiency anemia (IDA). Methods This was a multicenter, national, single‐arm, open‐label study. Children aged 6–53 months presenting with mild or moderate IDA (i.e., blood hemoglobin (Hb) ranging from 7.0 to 10.9 g/dL and serum ferritin <12 ng/mL) were eligible for inclusion. The ferrous sulfate heptahydrate solution (2 mg/kg/day) was administered orally for 3 months. If normalization of either Hb or ferritin was not achieved at month 3 the treatment was continued for another 3 months. Results Of the 100 children screened, 21 aged 6–17 months were included and received the study treatment, and 19 were analyzed for hematologic outcomes at month 3. Only one patient continued treatment for the additional 3 months. At month 3, mean ± SD Hb and ferritin levels were 12.0 ± 0.7 g/dL and 31.5 ± 19.4 ng/mL, respectively. Hemoglobin and ferritin levels were normalized in 95% (18/19) and 84% (16/19) of the patients, respectively. Treatment compliance and levels of satisfaction of both the parents and the investigators were high. Overall, 33.3% of patients (7/21) experienced at least one adverse event. Only one patient (4.8%) experienced a drug‐related adverse event (upper abdominal pain). Conclusions A 2 mg/kg daily dose of the new oral ferrous sulfate heptahydrate solution provides substantial therapeutic benefit with high levels of tolerability in young children who have mild or moderate IDA.

Introduction: Xerosis is a common skin side effect of current anticancer therapies, including chemotherapy, targeted therapy, radiotherapy, and hormonotherapy. We evaluated the effectiveness of an emollient PLUS containing an Aquaphilus dolomiae extract (ADE-G1) for the management of xerosis in adult patients treated for cancer. Methods: This real-world, prospective, observational, multicenter study involved 319 xerotic cancer patients, who were prescribed the study product according to the usual practice of their physician. The practitioner assessed xerosis severity and objective clinical signs, and the patients assessed subjective clinical signs and the impact of their skin condition on their quality of life, at inclusion and after around 4 weeks of use. Overall effectiveness and tolerance were assessed at the end of the study. Clinical success was defined by the combination of several of these effectiveness outcomes. Results: Daily application of the emollient PLUS reduced xerosis severity in 62.7% of patients (p \ 0.0001). The mean total severity scores for objective and subjective clinical signs were reduced by 67.7% and 57.4% (p \ 0.0001), respectively, compared with baseline. The mean Dermatology Life Quality Index (DLQI) score also significantly improved at the end of followup (-56.6%, p \ 0.0001). The product was rated as ''effective'' or ''very effective'' by the physician for over 80% of patients, regardless of the initial severity grade of xerosis. Overall clinical success was achieved in 73.7% of patients. A trend toward higher effectiveness and clinical success was observed in patients under hormonotherapy. The study product was well tolerated, regardless of the anticancer therapy being received. Conclusion:This study shows that the emollient PLUS containing ADE-G1 is an effective treatment for xerosis in cancer patients, regardless of the initial grade of xerosis and the anticancer treatment received.

One of the major concerns for chemotherapy is the selective targeting of drugs into highly proliferative cancer cells. Natural polyamines (spermine, spermidine, putrescine) are essential for the regulation of cellular growth and differentiation. Due to their highly proliferative nature, cancer cells have a pronounced need to import polyamines from their external environment, through the polyamine transporter system (PTS). On the basis of this biological mechanism, we vectorized the new cytotoxic anticancer compound F14512, a epipodophyllotoxin — spermine conjugate, into tumor cells.1 Here we present the synthesis and the structure-activity relationships of a new series of compounds constituted by an podophyllotoxin core tethered with a polyamine moiety with a variable spacer. Two synthetic strategies with protected polyamines, and a direct 3 steps synthesis of F14512 from natural podophyllotoxin and spermine without any protection are presented.2 This series of topoisomerase II inhibitors were checked for their cytotoxicity on A549 lung cancer cell line, displaying marked potency up to nM range. Cancer cell internalization through PTS was assessed by selective cytotoxicity on different PTS expressing cell lines, and by competition experiments. Our results displayed a potent specificity for the conjugated tetramine (spermine) compounds, which were more recognized than the triamine (spermidine) ones, while mono and diamines showed no selectivity. Lead compounds were also tested in vivo and proved potent antitumor activity. This series of new water-soluble cytotoxic compounds culminates with the selection of F14512 for clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A87.

F14512 is a novel polyamine-vectorized topoisomerase II inhibitor currently in phase 1/2 clinical trial in acute myeloid leukemia (AML). Since ABCB1 (also called P-glycoprotein or MDR1) has been reported to be expressed at high levels in patients with resistant leukaemia cells, and constitutes a pejorative marker of therapy, we decided to investigate whether F14512 could be exported by ABCB1 or other ABC transporters susceptible to confer drug resistance to chemotherapy, such as MRP1. In addition, we established a F14512-resistant cell line to study the mechanism of resistance to the drug. With membrane preparation enriched in functional MDR1, we found that F14512 was unable to stimulate the ATPase activity of this transporter. Using a cellular assay over expressing MDR1 transporter by recombinant transfection of MDCKII cells, F14512 was detectable, but the intracellular level was unchanged regardless of the MDR1 status or in presence of MDR1 competitors. Consistently, iterative selection of a F14512-resistant A-549 cell line with 36 cycles of F14512 at cytotoxic doses (0.5 EC50) over 9 months, led to only moderate shift of resistance (9 fold). In the resulting selected A-549 subclones, MDR1, MRP1 and ABCG2 were detectable at the basal level. The ability of F14512 to bypass MDR1 was finally assessed in a vinorelbine-resistant P388 model overexpressing high level of functional ABCB1 as indicated with the positive rhodamine export assay and cross resistance to MDR1 substrate. Moreover, F14512 displays strong antileukemic activity in MDR1-positive P388 cells in vitro and additional in vivo measurements are in progress. In conclusion, the data concur to show that the antitumor activity of the targeted cytotoxic agent F14512 is not impacted by the MDR1 status of cancer cells. MDR1 clearly does not affect the potency of F14512 and this characteristic augurs well for the ongoing development of the drug in AML patients. Citation Format: Jean Philippe Annereau, Viviane Brel, William Riquet, Laurent Créancier, Isabelle Vandenberghe, Emmanuel Fournier, Céline Robichon, Aline Stennevin, Vanessa Offrete, Laurence Lacastaigneratte, Bruno Gomes, Anna Kruczynski, Christian Bailly, Nicolas Guilbaud. F14512, a novel vectorized topoiserase II inhibitor, bypasses MDR1 mediated resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2013-988

Background Dermocosmetic products are often used to maintain or enhance the tolerance and effectiveness of medical anti‐acne therapies. Recent discoveries about the pathophysiology of acne‐prone skin indicate that skincare products may help maintain homeostasis around the sebaceous gland progenitor cells, thereby preventing microcomedone formation. Aims To evaluate the tolerance and effectiveness of a dermocosmetic product containing Silybum marianum fruit extract (SMFE) in adolescents and young adults with acne‐prone skin. Patients/Methods This real‐life, international, observational, multicenter study was conducted in patients aged 12–25 years with mild‐to‐moderate acne. Patients (N = 4230) used the product twice daily for 8–12 weeks, either alone before (“initial group”) or after an anti‐acne therapy (“maintenance group”), or in association with their usual prescribed anti‐acne therapies (“association group”). The tolerance, effectiveness, and cosmetic properties of the product were assessed. Patient quality of life (QoL) was also evaluated. Results Dermatologists rated the tolerance of the product as “good” or “very good” in about 95% of the patients and the effectiveness of the product as “effective” or “highly effective” in about 80% of the patients, with a significant reduction in the mean global evaluation of acne (GEA) grade (−36% ± 39%, p < 0.0001) at study end. The QoL of most patients (80%) improved by the end of the study, and the majority (79% to 94%) appreciated the cosmetic properties of the product. Overall, the product was a clinical success in >84% of patients. Conclusions This dermocosmetic product can be used by adolescents and young adults with acne‐prone skin to limit the initial or chronic use of medical anti‐acne therapies.