Anti-cancer effect of bio-reductive drug beta-lapachon is enhanced by activating NQO1 with heat shock.
OBJECTIVE
Bio-reduction/activation of anti-cancer drug beta-lapachone (beta-lap) is mediated by NAD(P)H: Quinone oxidoreductase (NQO1). We investigated the feasibility of using mild temperature hyperthermia to increase the anti-cancer effect of beta-lap by up-regulating NQO1 expression.


METHODS
NQO1 expression in FSaII fibrosarcoma of C3H mice and A549 human lung cancer cells was evaluated with Western blot analysis and immunostaining of cells at different times after water-bath heating. Clonogenic cell survival method was used to determine the sensitivity of cells to heating, beta-lap, and in combination. The growth of FSaII tumors in the right hind legs of C3H mice was studied after heating the tumors at 42 degrees C for 1 h with water bath, an i.p. injection of beta-lap to host mice or an i.p. injection of beta-lap 24 h after heating the tumors.


RESULTS
Heating at 42 degrees C for 1 h significantly increased the expression of NQO1 in the cancer cells with a maximum increase occurring 8-24 h after heating. The sensitivity of cancer cells to beta-lap treatment progressively increased until 24 h after heating most likely due to the increase in NQO1 expression. Heating the FSaII tumors at 42 degrees C for 1 h and treating the host mice with an i.p. injection of 50 mg/kg beta-lap 24 h after the tumor heating was far more effective than heating alone or beta-lap treatment alone to suppress the tumor growth.


CONCLUSIONS
Mild temperature heat shock elevates the NQO1 expression in cancer cells, which in turn markedly increases the sensitivity of the cells to the bioreductive drug beta-lap in vitro and in vivo.
Song
Chang W
CW
Radiobiology Laboratory, Department of Therapeutic Radiology, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA. songx001@umn.edu
Chae
Jongsun J
JJ
Choi
Eun K
EK
Hwang
Tae S
TS
Kim
Chulhee
C
Lim
Byung Uk
BU
Park
Heon Joo
HJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D020360:Neoadjuvant Therapy / Q000379:methods; D013696:Temperature
D000970:Antineoplastic Agents; D009285:Naphthoquinones; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase