Di‐2‐pyridylhydrazone Dithiocarbamate Butyric Acid Ester Exerted Its Proliferative Inhibition against Gastric Cell via ROS‐Mediated Apoptosis and Autophagy

Abstract

Diversified biological activities of dithiocarbamates have attracted widespread attention; improving their feature or exploring their potent action of mechanism is a hot topic in medicinal research. Herein, we presented a study on synthesis and investigation of a novel dithiocarbamate, DpdtbA (di-2-pyridylhydrazone dithiocarbamate butyric acid ester), on antitumor activity. The growth inhibition assay revealed that DpdtbA had important antitumor activity for gastric cancer (GC) cell lines (IC50 = 4.2 ± 0.52 μM for SGC-7901, 3.80 ± 0.40 μM for MGC-803). The next study indicated that growth inhibition is involved in ROS generation in mechanism; accordingly, the changes in mitochondrial membrane permeability, apoptotic genes, cytochrome c, bax, and bcl-2 were observed, implying that the growth inhibition of DpdtbA is involved in ROS-mediated apoptosis. On the other hand, the upregulated p53 upon DpdtbA treatment implied that p53 could also mediate the apoptosis. Yet the excess generation of ROS induced by DpdtbA led to cathepsin D translocation and increase of autophagic vacuoles and LC3-II, demonstrating that autophagy was also a contributor to growth inhibition. Further investigation showed that DpdtbA could induce cell cycle arrest at the G1 phase. This clearly indicated the growth inhibition of DpdtbA was via triggering ROS formation and evoking p53 response, consequently leading to alteration in gene expressions that are related to cell survival.

DpdtbA-Induced Growth Inhibition in Human Esophageal Cancer Cells Involved Inactivation of the p53/EGFR/AKT Pathway

“…To extend our knowledge for the dithiocarbamate derivative, the effect of DpdtbA on the proliferation of esophageal cancer cell lines was further investigated. Interestingly, the DpdtbA-induced growth inhibition involved p53 depletion, which was not consistent with that reported previously in gastric cancer cell lines [24]. Additional investigations revealed that the p53 degradation was through chaperon-mediated autophagy rather than MDM2-mediated ubiquitination.…”

“…As shown in Figure 2, DpdtbA caused an accumulation of the ESC cells in the S phase for both cell lines, and the percentages at the S phase significantly increased by 10 to 17% during 24 h insult of the agent, thereby decreasing the proportion of cells in the G1 phase. Those indicated that DpdtbA could disturb cell cycle and arrest the cells at the S phase, which was not consistent with that in gastric cell lines [24], indicating that DpdtbA-induced cell cycle delay was cell line dependent. Furthermore, it was well documented that the progression of cells is regulated by cyclins and CDK (cyclin-dependent kinase) proteins, and cyclin A and CDK2 are known to play an important role in the regulation of DNA synthesis during cell-cycle progression at the S phase; thus, the expression of CDK2 in different conditions was determined.…”

“…Previous study demonstrated that di-2,2′-pyridine ketone dithiocarbamate s-butyric acid (DpdtbA) owned significant growth inhibition in gastric cell lines [24]; DpdtbA might have similar action in ESC cell lines. With this purpose, we first assessed the effect of DpdtbA on the cell viability of Kyse 450, 150, and 510 cells.…”

“…Dithiocarbamates as metal chelators own important biological activities in the treatment of bacterial and fungal infections, AIDS, and cancer [23]. DpdtbA (di-2,2′-pyridine ketone dithiocarbamate s-butyric acid), a dithiocarbamate derivative, also displayed significant growth inhibition against gastric cancer cell lines in our previous study [24]. To extend our knowledge for the dithiocarbamate derivative, the effect of DpdtbA on the proliferation of esophageal cancer cell lines was further investigated.…”

Growth Inhibition of a Novel Iron Chelator, DpdtC, against Hepatoma Carcinoma Cell Lines Partly Attributed to Ferritinophagy‐Mediated Lysosomal ROS Generation

“…Cells were seeded into a 6-well plate and treated as described above for the cell viability assay. The cells were treated with either the agent alone (1.0 or 2.0 μ M) or a combination with 3-MA (1.5 mM) or NAC (1.5 mM)) for 24 h. Then, the cell culture was removed, following PBS washing, trypsin digestion; finally, the MDC (50 μM) were added as described previously [ 47 ]. The stained cells were subjected to flow cytometric analysis (Becton-Dickinson, USA).…”