Naftopidil is clinically for treatment of benign prostate
hyperplasia, and emerging evidence has pointed to its anticancer effect. To obtain the anticancer
drug with the potential greater than that of
naftopidil, we have newly synthesized the
naftopidil analogue
HUHS1015. The present study investigated the mechanism underlying HUHS1015-induced apoptosis of human
gastric cancer cells and assessed the possibility for clinical use as an innovative anticancer
drug.
HUHS1015 reduced cell viability for MKN28 human well-differentiated gastric
adenocarcinoma cell line and MKN45 human poorly differentiated gastric
adenocarcinoma cell line in a concentration (0.3-100 μM)-dependent manner more effectively than
cisplatin, a chemo-
drug widely used. In the flow cytometry using
propidium iodide (PI) and
annexin V,
HUHS1015 significantly increased the population of PI-positive and
annexin V-negative cells, corresponding to primary
necrosis and that of PI-positive and
annexin V-positive cells, corresponding to late apoptosis/secondary
necrosis, both in the two cell types.
HUHS1015 significantly activated
caspase-3, caspase-4, and
caspase-8 in MKN45 cells, while no obvious
caspase activation was found in MKN28 cells.
HUHS1015 upregulated expression of the
tumor necrosis factor α (TNFα)
mRNA and
protein in MKN45 cells, allowing activation of
caspase-8 through
TNF receptor and the effector
caspase-3.
HUHS1015 clearly inhibited
tumor growth in mice inoculated with MKN45 cells, with the survival rate higher than that for the anticancer drugs
cisplatin,
paclitaxel, and
irinotecan. The results of the present study show that
HUHS1015 induces
caspase-independent and caspase-dependent apoptosis of MKN28 and MKN45 human
gastric cancer cells, respectively, and effectively suppresses MKN45 cell proliferation.