A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines HEK293 (human embryonic kidney), MCF7 (human breast adenocarcinoma), HTB81 (human prostate carcinoma), HeLa (human epithelioid cervix carcinoma), RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma), and A549 (carcinomic human alveolar basal epithelial cell). Given the possibilities in the diversity of the substituents that offer the multicomponent synthetic methodology, an extensive structure-activity profile is presented. In addition, both enantiomers of phosphonate-derived γ-lactam have been synthesized and isolated and a study of the cytotoxic activity of the racemic substrate vs. its two enantiomers is also presented. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.

Mucosa-Associated Lymphoid Tissue 1 Is an Oncogene Inducing Cell Proliferation, Invasion, and Tumor Growth via the Upregulation of NF-κB Activity in Human Prostate Carcinoma Cells

Prostate cancer is one of the most common seen malignancies and the leading cause of cancer-related death among men. Given the importance of early diagnosis and treatment, it is worth to identify a potential novel therapeutic target for prostate cancer. Mucosa-associated lymphoid tissue 1 (MALT1) is a novel gene involved in nuclear factor κB (NF-κB) signal transduction by acting as an adaptor protein and paracaspase, with an essential role in inflammation and tumorigenesis in many cancers. This study investigated the functions and the potential regulatory mechanisms of MALT1 in the human prostate cancer cells. We found that MALT1 is abundant in prostate cancer tissues. MALT1 facilitated NF-κB subunits (p50 and p65) nuclear translocation to induce gene expression of interleukin 6 (IL-6) and C-X-C motif chemokine 5 (CXCL5) in prostate carcinoma cells. MALT1 promoted cell proliferation, invasion, and tumor growth in vitro and in vivo. MALT1 enhanced NF-κB activity in prostate carcinoma cells; moreover, NF-κB induced MALT1 expression determined by reporter and immunoblot assays, implying there is a positive feedback loop between MALT1 and NF-κB. In conclusion, MALT1 is a NF-κB-induced oncogene in the human prostate carcinoma cells.

Cytotoxicity of Mitomycin C-Porous Silicon in Human Prostate Carcinoma Cells

Porous silicon (pSi) microparticles with pore diameter 15 to 20 nm were fabricated by electrochemical etching of single-crystalline silicon (Si) wafers (n-type) to be used as delivery systems for the anticancer drug mitomycin C (MMC). The in vitro toxicity of the mitomycin-loaded pSi carrier was investigated on human prostate carcinoma (DU145) cells. The cells showed a decrease in viability of ~80% over a 6 hours period, when using mitomycin. Meanwhile, a ~55% decrease in cell viability was observed, when using the pSi carrier to deliver the drug. The drug-loaded carrier showed a sustained release throughout 24 hours, with an 80% decrease in cell viability after 16 hours. This observed controlled release of mitomycin from the pSi carrier suggests a superior therapeutic effect than the direct administration of mitomycin, as it potentially minimizes the drug side effects. Results showed that the strong cytotoxic effect towards the prostate cancer cells was due to the drug and not the carrier since the mitomycin-loaded pSi carrier affected cell viability, but the pSi carrier showed no toxicity. Furthermore, it was observed that with a higher amount of drug-loaded carriers, the toxicity effect was higher, thus, allowing further control of the therapeutic effect of the carrier.