Quinoides and VEGFR2 TKIs influence the fate of hepatocellular carcinoma and its cancer stem cells

Abstract

Bioactivities of quinoides and VEGFR2 TKIs in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC values in μM concentrations in HCC cells. Quinoide was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor. However, the more cytotoxic VEFGR TKIs (IC: 0.4-3.0 μM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor () was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

“…Markers validated for the identification of LCSCs include CD133, EpCAM, CD90, CD44, CD24, CD13, and OV6 as well as Hoechst dye efflux or aldehyde dehydrogenase (ALDH) activity (7). In our previous study, it was well defined that CD133 and EpCAM were convenient to detect LCSCs of epithelial like (well-differentiated) cells, whereas CD90 was efficient to detect LCSCs of mesenchymal like (poorly differentiated) cells (8,9).…”

Synthesis of novel 6-substituted amino-9-(β-d-ribofuranosyl)purine analogs and their bioactivities on human epithelial cancer cells

“…[14][15][16][17] Therefore, it is essential to identify new candidate therapeutic agents for hepatocellular carcinoma. 18,19 We have previously exploited purine and purine nucleoside derivatives, which have displayed promising cytotoxic activities in liver cancer cells. The molecules from those studies had significant bioactivities on liver cancer cells.…”

“…These molecules were then synthesized as a new series of 6-substituted amino-9-(b-D-ribofuranosyl)purine derivatives (9-22, 27, 28) and their cytotoxic activities were screened in human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7). The bioactivities of the most potent nucleoside derivatives (11,13,16,18,19,21,27,28) were further analyzed in hepatocellular cancer cell lines (see Figure 1).…”

“…25 The IC 50 values for each compound also were calculated in comparison with the known nucleobase analog 5-fluorouracil (5-FU), nucleoside analogs fludarabine and cladribine and the results were shown in Table 1. Among the synthesized compounds, analogs accommodating substituted piperazine moiety at their C-6 position (9-16, 27), the one with promising IC 50 values against Huh7 We then analyzed the cytotoxic activities of the most potent nucleoside derivatives (11,13,16,18,19,21,27,28) in a panel of HCC cells: Huh7, HepG2, Mahlavu, and FOCUS ( Table 2) In silico ADME parameters of the new nucleoside analogs 9-22, 27-28, were used to calculate Lipinski's rules, solubility, percentage of absorption (%ABS) and topological polar surface area (TPSA) ( Table 3) (see Supplementary documentation). All compounds have molecular weights smaller than 500 (377.44 > MW < 447.47), with the exception of the compounds 16 and 27.…”

“…EtOH, 17 22%, 18 20%, 19 54%, 20 24%; (vi) 2-substituted ethyl amines, Et 3 N, EtOH, 21 10%, 22 10%; (vii) 1,2,3,5-tetra-O-acetyl-b-D-ribofuranose, silica gel 60, EtOAc, microwave irradiation, 120 W, 24 79%; (viii) 1-(a,a,a-trifluoro-p-tolyl)piperazine, TEA, EtOH, 25 75%; (ix) 2-(1-cyclohexenyl) ethylamine, TEA, EtOH, 26 62%; (x) NaOMe, MeOH, 27 87%, 28 40%. (HCC), the bioactivities of the compounds11,13,16,18,19,21, 27, 28 were further tested on a panel of liver cancer cell lines. Compound 21 and 27, which were designed as putative anticancer agents, showed the best biological activities with IC 50 values of 1-3 lM on HepG2 liver cancer cells.…”