Inhibitory Effects of The Botanical Alkyl Hydroquinone Derivative HQ17(3) on Acute Lymphoblastic Leukemia Cell Lines
Date Issued
2016
Date
2016
Author(s)
Chen, Chia-Wei
Abstract
Acute lymphoblastic leukemia (ALL), the most common cancer in childhood, is a neoplasm with uncontrolled proliferation of immature B- or T-lymphoid cells in hematopoietic system. Aberrant expression of proto-oncogene, chromosome translocation or hyperdiploidy make hematopoietic stem cell (HSC) or progenitor cells obtain ability of uncontrolled proliferation, anti-apoptosis and self-renewal and result in ALL development. High risk (HR) precursor B-ALL with t(9;22) BCR-ABL composed of 3% of childhood ALL and more than 25% of the adult ALL. It’s characterized by dismal clinical outcome, even treated with the highest dose chemotherapy combined with tyrosine kinase inhibitors (e.g. Imatinib, IM). Resistant to first-line drugs (e.g. glucocorticoid, Dexamethasone) is a common problem encountered in T-ALL treatment. Developing new therapeutic strategies for high risk ALL is necessary. The small natural molecule 10’(Z),13’(E),15’(E)- heptadecatrienyl hydroquinone (HQ17(3)) is extracted from the sap of the lacquer tree Rhus succedanea. HQ17(3) exerted selective cytotoxicity in various types of cancer cells, but did not reduce the viability of normal peripheral blood leukocytes. Introduction of HQ17(3) resulted in DNA topoisomerase II inhibition and oxidative stress production in Huh7 cell lines. We found HQ17(3) had significant cytotoxic effect within 24 hours at micromolar concentration on HR SUP-B15 (IM-refractory BCR-ABL+ B-ALL) and Jurkat (Dexamethasone-resistant T-ALL) cell lines. HQ17(3) lead to loss of mitochondria membrane potential and caspase-dependent cell death in Jurkat cells. HQ17(3) induced caspase-independent cell death in SUP-B15 cells. Combination of sub-IC50 concentration of HQ17(3) sensitize SUP-B15 cells to Imatinib, and enhance the inhibitory effect of Dexamethasone on Jurkat cells. In SUP-B15 cells, HQ17(3) induced formation of acidic vesicles prior to cell death. The cause of HQ17(3)-induced cell death could not be attributed to cathepsins from lysosomal membrane permeabilization (LMP) because cathepsin inhibitors did not attenuate the cell death. HQ17(3) induced autophagy characterized by aggregation of ectopically expressed EGFP-LC3. Inhibition of autophagy by Bafilomycin A1 or knockdown the essential autophagy-related protein Beclin1 by shRNA could partially attenuate HQ17(3)-induced cell death. Autophagy induced by rapamycin also reduced the cytotoxic effect of HQ17(3). HQ17(3)-induced autophagy may be implicated cell death. Further, HQ17(3) treatment gave rise to early mTOR and NF-B activation, indicating induction of cell stress. HQ17(3) also induce ER stress as revealed by enhancement of eIF2 phosphorylation and up-regulation of ER chaperone Grp78. We speculate HQ17(3) may lead to ER stress and then result in autophagy and cell death. In summary, HQ17(3) is highly cytotoxic to high risk ALL cell lines (SUP-B15 and Jurkat), and combination of HQ17(3) with the first-line anti-leukemia drugs enhance the inhibitory effect on ALL cells. HQ17(3) also induced ER stress and autophagy in SUP-B15. Whether ER stress is essential for HQ17(3)-induced autophagy and cell death in BCR-ABL+ B-ALL cells await further investigation.
Subjects
ALL
autophagy
ER stress
SDGs
Type
thesis
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