Vitamins K1 and K2 potentiate hyperthermia by down-regulating Hsp72 expression in vitro and in vivo.
Hyperthermia is used to treat various malignancies, including esophageal, stomach and rectal cancer. Since hyperthermia alone has produced limited results, much attention has been focused on combining hyperthermia with chemotherapy and on searching for substances able to sensitize tumor cells to hyperthermia-induced damage. Here, we show that vitamins K1 and K2 (VK1, VK2) inhibited the expression of heat-shock protein 72 (Hsp72) but did not affect the constitutive expression of Hsc70 or calnexin in vitro and in vivo. VK1 and VK2 sensitized A549 cells to heat-shock induced cell death, while the compounds alone had no effect on cell viability. The suppression of Hsp72 was apparently at the protein level because the mRNA expression of Hsp72 was unchanged. Moreover, the chaperone activity of Hsp72 was compromised after heat-shock when cells were pre-treated with VK2. The effect of VK2 on Hsp72 suppression, however, was also observed in normal mouse tissue after the mice were subjected to whole-body hyperthermia. To eliminate this side effect, local hyperthermia was performed on tumors in mice. The pre-treatment with VK2 potentiated the effect of local hyperthermia on tumor growth suppression. The findings here that VK1 and VK2 inhibit heat-shock-induced Hsp72 suggest their possible use as an adjuvant for hyperthermia in cancer therapy.
Shimohara
Shuji
S
Department of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Murakami
Toru
T
Morikawa
Mari
M
Matsuo
Junko
J
Nagayama
Shin-Ichi
S
Shuto
Tsuyoshi
T
Suico
Mary Ann
MA
Okiyoneda
Tsukasa
T
Yamatsu
Isao
I
Mizushima
Toru
T
Shimasaki
Tatsuya
T
Kai
Hirofumi
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D008156:Luciferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D010837:Vitamin K 1 / Q000494:pharmacology; D024482:Vitamin K 2 / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D050884:HSP72 Heat-Shock Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014815:Vitamins; D024482:Vitamin K 2; D010837:Vitamin K 1; D008156:Luciferases