This work was partly supported by the grant from the research program ‘‘Fundamentals of Genomics and Proteomics’’ No. 107U002244 of National Academy of Sciences of Ukraine. We would like to thank Dr. N. Khranovskaya for her help with flow cytometry.

Despite the extensive work on pathological mechanisms and some recent advances in the treatment of different hematological malignancies, leukemia continues to present a significant challenge being frequently considered as incurable disease. Therefore, the development of novel therapeutic agents with high efficacy and low toxicity is urgently needed to improve the overall survival rate of patients. In this comprehensive review article, the current knowledge about the anticancer activities of flavonoids as plant secondary polyphenolic metabolites in the most commonly used human established leukemia cell lines (HL-60, NB4, KG1a, U937, THP-1, K562, Jurkat, CCRF- CEM, MOLT-3, and MOLT-4) is compiled, revealing clear anti-proliferative, pro-apoptotic, cell cycle arresting, and differentiation inducing effects for certain compounds. Considering the low toxicity of these substances in normal blood cells, the presented data show a great potential of flavonoids to be developed into novel anti-leukemia agents applicable also in the malignant cells resistant to the current conventional chemotherapeutic drugs.

background

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Apoptosis and content of mobile lipid domains in human leukemia K-562 cells induced to differentiate by quercetin or dimethyl sulfoxide.

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids.

Background
Multidrug resistance is the main obstacle to the efficiency of systemic chemotherapy against hematologic malignancy. This study investigated the reversible effect of the copolymer wogonin and daunorubicin coloaded into Fe3O4 magnetic nanoparticles, and the mechanism potentially involved.

methods

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Effect of magnetic nanoparticles of Fe3O4 and wogonin on the reversal of multidrug resistance in K562/A02 cell line

Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (abl) protooncogene on chromosome 9 with 5′ sequence of truncated break point cluster region (bcr) to chromosome 22. The fusion gene product BCR-ABL, a functional oncoprotein p210, is a constitutively activated tyrosine kinase that activates several cell proliferative signaling pathways. BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib and ponatinib potently inhibit CML progression. However, drug resistance owing to BCRABL mutations and overexpression is still an issue. Natural products are chemical compounds or substances produced by living organisms. They are becoming an important research area for cancer drug discovery due to their low toxicity and cost-effectiveness. Several lines of evidence show that many NPs such as alkaloids, flavonoids, terpenoids, polyketides, lignans and saponins inhibit CML cell proliferation and induce apoptosis. NPs not only differentiate CML cells into monocyte/erythroid lineage but also can reverse the multi-drug resistance (MDR) in CML cells. In this chapter, we review the anti-CML activity of various NPs.

/pdf/natural-products-for-treatment-of-chronic-myeloid-leukemia-4zqhh0f3z4.pdf

Natural Products for Treatment of Chronic Myeloid Leukemia

Background: While multidrug resistance of cancer cells is a well-known phenomenon, little is known on the cross resistance between cytotoxic chemotherapeutical agents and unrelated substances such as natural flavonoids. Aim: To compare the effects of cytotoxic drug, vepeside and natural flavonoid, quercetin in Jurkat cells and their multidrug-resistant subline Jurkat/A4, in particular to analyze the effector mechanisms of apoptosis and the profiles of several pro- and antiapoptotic proteins in these cells upon exposure to vepeside or quercetin. Methods: Apoptosis and poly (ADP-ribose) polymerase cleavage were assessed by flow cytometry. Expression of apoptosisrelated proteins was analyzed by Western blotting. Results: Jurkat/A4 cells are less sensitive to antiproliferative effects of quercetin as compared with the parental Jurkat cell line. While vepeside as well as quercetin initially induces apoptosis in both cell lines, the following survival of the exposed cells is essentially different. In resistant Jurkat/A4 cells, vepeside or quercetin treatment activates significantly less caspase-9 and -3 as compared with that in the parental cells. The expression of Bad and BNip1 proteins in Jurkat/A4 cells is lower than in the parental cell line. At the same time, XIAP and CAS levels in Jurkat/A4 cells increase. Upon apoptosis induction, XIAP and CAS levels in Jurkat cells decrease, this effect being negligible in resistant cells. Conclusion: Multidrug-resistant Jurkat/A4 cells exhibit reduced sensitivity to cytotoxic effects of quercetin. The expression profile of Jurkat/A4 cells is characterized by the increased levels of XIAP and CAS representing the endogenous inhibitors of apoptosis.

/pdf/jurkat-a4-cells-with-multidrug-resistance-exhibit-reduced-58zl24odhe.pdf

Apoptosis and content of mobile lipid domains in human leukemia K-562 cells induced to differentiate by quercetin or dimethyl sulfoxide.

Citations

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids.

Effect of magnetic nanoparticles of Fe3O4 and wogonin on the reversal of multidrug resistance in K562/A02 cell line

Natural Products for Treatment of Chronic Myeloid Leukemia

Jurkat/A4 cells with multidrug resistance exhibit reduced sensitivity to quercetin.

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Acetyl derivate of quercetin increases the sensitivity of human leukemia cells toward apoptosis