Differential sensitivity of leukemic and normal hematopoietic progenitors to the killing effect of hyperthermia and quercetin used in combination: role of heat-shock protein-70.
Autologous bone-marrow transplantation (ABMT) is widely used in the treatment of acute leukemias where a matched sibling donor is not available for allogeneic transplantation. However, a major problem in ABMT is relapse, and ex vivo purging may be very important in preventing it. We show here that quercetin enhances the growth-inhibitory effect of hyperthermia (HT) in AML (19 cases) and ALL (6 cases) leukemic blasts. Furthermore, the inhibitory effect of this combined treatment resulted in leukemic-cell apoptosis. On the contrary, normal hematopoietic progenitors were neither growth-inhibited nor induced to apoptosis by HT-plus-quercetin treatment. To explain this difference in sensitivity of leukemic and normal hematopoietic progenitors, we analyzed the effect of quercetin on heat-induced expression of heat-shock protein-70 (HSP-70), which has been shown to be important in regulating thermosensitivity. We found that quercetin inhibits heat-induced HSP-70 expression both at protein and at mRNA levels in AML and ALL blasts. In normal CD34+ progenitors, the combined treatment with HT and quercetin did not reduce HSP-70 expression and did not induce cell apoptosis. Considering the difference in heat sensitivity of normal CD34+ and leukemic progenitors in the presence of quercetin, the combined use of HT and quercetin could constitute a purging protocol for ABMT.
Larocca
L M
LM
Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy.
Ranelletti
F O
FO
Maggiano
N
N
Rutella
S
S
La Barbera
E O
EO
Rumi
C
C
Serra
F
F
Voso
M T
MT
Piantelli
M
M
Teofili
L
L
Leone
G
G
D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D003131:Combined Modality Therapy; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D006979:Hyperthermia, Induced; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000628:therapy*; D011794:Quercetin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D018840:HSP70 Heat-Shock Proteins; D011794:Quercetin