Lycorine, the Main Phenanthridine Amaryllidaceae Alkaloid, Exhibits Significant Antitumor Activity in Cancer Cells That Display Resistance to Proapoptotic Stimuli: An Investigation of Structure−Activity Relationship and Mechanistic Insight

Abstract

Twenty-two lycorine-related compounds were investigated for in vitro anti-tumor activity using four cancer cell lines displaying different levels of resistance to pro-apoptotic stimuli and two cancer cell lines sensitive to pro-apoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro anti-tumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at non-toxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to pro-apoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, metastatic cancers, among others.

N-Aryl-N′-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis

“…As the in vitro growth inhibitory activity of the compounds under study were analyzed on human glioma cell lines, while the bioselectivity was determined on mouse normal astrocytes, we also analyzed the in vitro growth inhibitory activity of the bioselective compounds detailed in Table 3 on a mouse melanoma pseudometastasis brain model [42] in order to rule out differences that could relate to interspecies features. The data in Table 3 clearly indicate that mouse and human cancer cells display similar sensitivity to the compounds under study.…”

Novel Lycorine Derivatives as Anticancer Agents: Synthesis and In Vitro Biological Evaluation

“…Hundreds of alkaloids have been isolated and extensively studied for their pharmacological properties since 1877 [7]. Lycorine is one of the most common alkaloids within Amaryllidaceae family of plants and reportedly exhibits promising anticancer properties [7][8][9][10][11][12].…”

Quercetin inhibits a large panel of kinases implicated in cancer cell biology

“…The overall growth levels of the human cancer cell lines were determined using the colorimetric MTT [3-(4,5-dimethylthiazol-2yl)]-diphenyltetrazolium bromide, Sigma, Belgium) assay (12)(13)(14)(15)(16)(17). Briefly, cell lines were incubated for 24 h in 96-microwell plates at concentrations of 10,000-40,000 cells/ml, depending on the cell type, to ensure adequate plating prior to making cell growth determinations.…”

“…The number of living cells after 72 h of culture in the presence (or absence for the negative control) of the various compounds was directly proportional to the intensity of the blue colour, which was measured quantitatively by spectrophotometry using a Bio-Rad Model 680XR (Bio-Rad, Nazareth, Belgium) at the 570-nm wavelength (with a reference wavelength of 630 nm). Each experimental condition was run six times (12)(13)(14)(15)(16)(17). Quercetin was obtained from Sigma (Bornem, Belgium), and quercetin-3-O-glucuronide (miquelianin) and quercetin-3-Ogalactoside (hyperoside) were obtained from Carbosynth (Compton, Berkshire, England).…”