Cellular uptake and antitumor activity of the new anthracycline analog DA-125 in human cancer cell lines

Abstract

To predict the clinical usefulness of DA-125, a newly developed doxorubicin analog, we compared its antitumor activity against 20 different human cancer cell lines with that of doxorubicin using the MTT in vitro chemosensitivity test. We also measured and compared the cellular uptake of this drug and doxorubicin in two cancer cell lines and their doxorubicin-resistant sublines. In the MTT test, DA-125 showed lower IC50 values than doxorubicin for 14 of 20 cell lines. DA-125 was more potent than doxorubicin for hepatocellular cancer cells with high mdr 1 expression. Among cancer cells from the stomach and colon, DA-125 was more potent than doxorubicin in 12 of 14 cell lines. We also investigated the cross-resistance of this drug with doxorubicin using four doxorubicin-resistant cancer cell sublines. Except in one cell line, there was very low cross-resistance. Cellular drug-uptake experiments were performed for two gastric cancer cell lines and their doxorubicin-resistant sublines. In this experiment, DA-125 was found to be very rapidly and completely converted to its active metabolite, M1, in the culture media. After this conversion, M1 was incorporated into these cancer cells more rapidly and reached higher intracellular concentrations than doxorubicin, suggesting that DA-125 (as M1) could achieve earlier and higher levels of intracellular accumulation than doxorubicin in its target tissues from the bloodstream. As a possible alternative antineoplastic agent to doxorubicin, DA-125 awaits further evaluation for its antitumor activity and toxicity.

Solvation of 1-Amino-4-Hydroxy-9,10-Anthraquinone Governs Its Electrochemical Behavior in Non-Aqueous and Aqueous Media: A Cyclic Voltammetry Study

“…2.303 RT [3] where, F = Faraday, R = molar gas constant, T = 298.15 K, n = number electron transferred in this reaction = 1, E 1 = formal potential of first reduction, E 2 = formal potential of second reduction. The values of apparent comproportionation constants (K comp ) are found to be 2.69 × 10 6 , 1.04 × 10 8 and 1.27 × 10 9 in ACN, DMF and DMSO respectively (Table I) indicating that semiquinone formation is enhanced with the increase in polarity of the medium.…”

“…Anthracycline drugs such as doxorubicin, daunorubicin, carminomycin, aclacinomycin, nogalamycin, etc., are some of the important chemotherapeutic agents used in the treatment of various forms of human cancers. [1][2][3][4] Since their discovery, studies on anthracycline antibiotics have been actively pursued for their anticancer activity and mechanism of drug action. Most of these studies on anthracyclines and its metal complexes concentrate on the interaction with DNA.…”

1-Amino-4-hydroxy-9,10-anthraquinone – An analogue of anthracycline anticancer drugs, interacts with DNA and induces apoptosis in human MDA-MB-231 breast adinocarcinoma cells: Evaluation of structure–activity relationship using computational, spectroscopic and biochemical studies

“…Anthracycline drugs are chemotherapeutic agents containing a planar hydroxy-9, 10-anthraquinone at the core of the molecule that is in use for the treatment of various human cancers [1] , [2] , [3] . Although there is controversy regarding the exact mechanism of action of these drugs as chemotherapeutics, various established pathways of drug action such as intercalation into DNA base pairs, inhibition of RNA transcription and DNA replication, inhibition of topoisomerase II, induction of DNA cleavage, etc., were observed to be associated with the interaction of such molecules with DNA [4] , [5] , [6] , [7] , [8] , [9] , [10] .…”

A Co(III) Complex of 1-Amino-4-hydroxy-9,10-anthraquinone Exhibits Apoptotic Action against MCF-7 Human Breast Cancer Cells

“…Anthracycline drugs are anticancer agents used in treating different forms of human carcinoma. − Although they enjoy wide acceptance in chemotherapy, their use is often questioned for the associated cardiotoxicity and high cost involved, particularly for people from economically weaker sections of the society. Hence, there is an effort worldwide − to find alternative cheaper analogues that are less cardiotoxic. − These are either derivatives of anthracyclines that are less costly or their simpler analogues. − …”