Etoposide-resistant HT-29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down-regulator.
Glucose deprivation, a pathophysiological cell condition, causes up-regulation of GRP78 and induction of etoposide resistance in human cancer cells. The induction of drug resistance can be partly explained by the fact that GRP78 can block activation of caspase-7 induced by treatment with etoposide. Therefore, downregulating GRP78 expression may be a novel strategy anticancer drug development. Based on that premise, we established a screening program for anticancer agents that exhibit preferential cytotoxic activity for etoposide-resistant cancer cells under glucose-deprived conditions. We recently isolated an active compound, AR-054, from the culture broth of Streptomyces sp., which prevents stress-induced etoposide resistance in vitro. AR-054 was identified as piericidin A, a prototypical compound, by ESI-MS analysis and various NMR spectroscopic methods. Here, we showed that piericidin A suppressed the accumulation of GRP78 protein and was also highly toxic to etoposide-resistant HT-29 cells, with IC50 values for colony formation of 6.4 and 7.7 nM under 2-deoxyglucose supplemented and glucose-deprived conditions, respectively. Interestingly, piericidin A had no effect under normal growth conditions. Therefore, we suggest that piericidin A prevents up-regulation of GRP78, and exhibits cytotoxicity in glucose-deprived HT-29 cells that are resistant to etoposide.
Hwang
Ji-Hwan
JH
Department of Food Science and Biotechnology, Kyungnam University, Masan, Korea.
Kim
Ju-Young
JY
Cha
Mi-Ran
MR
Ryoo
In-Ja
IJ
Choo
Soo-Jin
SJ
Cho
Sung-Min
SM
Tsukumo
Yoshinori
Y
Tomida
Akihiro
A
Shin-Ya
Kazuo
K
Hwang
Yong-Il
YI
Yoo
Ick-Dong
ID
Park
Hae-Ryong
HR
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D011725:Pyridines / Q000302:isolation & purification / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011725:Pyridines; D005047:Etoposide; C100213:piericidin A; D053179:Caspase 7; D005947:Glucose