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Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 3, pp 527–535

First Online: 08 January 2015Received: 18 July 2014Accepted: 22 December 2014DOI: 10.1007-s00280-014-2661-z

Cite this article as: Kaku, Y., Tsuchiya, A., Kanno, T. et al. Cancer Chemother Pharmacol 2015 75: 527. doi:10.1007-s00280-014-2661-z

Abstract

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.

KeywordsHUHS1015 Anticancer drug Gastric cancer Apoptosis Suppression of tumor growth AbbreviationsHUHS10151-2-2-Methoxyphenylaminoethylamino-3-naphthalene-1-yloxypropan-2-ol

MTT3-4,5-Dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide

PIPropidium iodide

RT-PCRReverse transcription-polymerase chain reaction

TNFαTumor necrosis factor α

HRPHorseradish peroxidase

LSDLeast significant difference

EREndoplasmic reticulum

FADDFas-associated death domain protein

TNFR1TNF receptor 1

TRADDTNFR1-associated death domain protein

Yoshiko Kaku and Ayako Tsuchiya have contributed equally to this work.

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Autor: Yoshiko Kaku - Ayako Tsuchiya - Takeshi Kanno - Shuhei Nakao - Tadashi Shimizu - Akito Tanaka - Tomoyuki Nishizaki

Fuente: https://link.springer.com/



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