Transmembrane (TMEM) protein family members: Poorly characterized even if essential for the metastatic process.

The majority of cancer-associated deaths are related to secondary tumor formation. This multistep process involves the migration of cancer cells to anatomically distant organs. Metastasis formation relies on cancer cell dissemination and survival in the circulatory system, as well as adaptation to the new tissue notably through genetic and/or epigenetic alterations. A large number of proteins are clearly identified to play a role in the metastatic process but the structures and modes of action of these proteins are essentially unknown or poorly described. In this review, we detail the involvement of members of the transmembrane (TMEM) protein family in the formation of metastases or in the mechanisms leading to cancer cell dissemination such as migration and extra-cellular matrix remodelling. While the phenotype associated with TMEM over or down-expression is clear, the mechanisms by which these proteins allow cancer cell spreading remain, for most of them, unclear. In parallel, the 3D structures of these proteins are presented. Moreover, we proposed that TMEM proteins could be used as prognostic markers in different types of cancers and could represent potential targets for cancer treatment. A better understanding of this heterogeneous family of poorly characterized proteins thus opens perspectives for better cancer patient care.

Design and Synthesis of a New Soluble Natural ß-Carboline Derivative for Preclinical Study by Intravenous Injection.

Harmine is a natural ß-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection.

Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia.

Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and chemotherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression. Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxia compared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells in normoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiate their activity in low oxygen environment could be a strategy to counteract this resistance. To identify new compounds active in hypoxia, we screened one hundred molecules with different chemical structures from an internal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently of their mechanism of action has been assayed. After a first step of selection, based on biological/pharmacological properties and chemical structure analysis, we identified three potential hits. Two hits are closely related amides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normal cells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death, the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol and etoposide in two models of cancer cell lines. This new compound could lead to the development of an original series of chemosensitizers active under hypoxia.