Abstract
Plants are a significant reservoir of cytotoxic agents, including compounds with the ability to interfere with multidrug-resistant (MDR) cells. With the aim of finding promising candidates for chemotherapy, 91 native and naturalized plants collected from the central region of Argentina were screened for their cytotoxic effect toward sensitive and MDR P-glycoprotein (P-gp) overexpressing human leukemia cells by means of MTT assays. The ethanol extracts obtained from Aldama tucumanensis, Ambrosia elatior, Baccharis artemisioides, Baccharis coridifolia, Dimerostemma aspilioides, Gaillardia megapotamica, and Vernonanthura nudiflora presented outstanding antiproliferative activity at 50 μg/mL, with inhibitory values from 93 to 100%, when tested on the acute lymphoblastic leukemia (ALL) cell line CCRF-CEM and the resistant derivative CEM-ADR5000, while 70–90% inhibition was observed against the chronic myelogenous leukemia (CML) cell K562 and its corresponding resistant subline, Lucena 1. Subsequent investigation showed these extracts to possess marked cytotoxicity with IC50 values ranging from 0.37 to 29.44 μg/mL, with most of them being below 7 μg/mL and with ALL cells, including the drug-resistant phenotype, being the most affected. G. megapotamica extract found to be one of the most effective and bioguided fractionation yielded helenalin (1). The sesquiterpene lactone displayed IC50 values of 0.63, 0.19, 0.74, and 0.16 μg/mL against K562, CCRF-CEM, Lucena 1, and CEM/ADR5000, respectively. These results support the potential of these extracts as a source of compounds for treating sensitive and multidrug-resistant leukemia cells and support compound 1 as a lead for developing effective anticancer agents.
Highlights
Leukemia is a malignant disorder with a significant number of deaths annually [1]
With the aim of finding new agents capable of interfering with the proliferation of sensitive and multidrug resistance (MDR) leukemia cells, 91 ethanol extracts obtained from different plant species of Central Argentina were primarily assayed at a fixed concentration of 50 μg/mL against a panel of cells consisting of CCRF-CEM and K562 and their respective P-gp overexpressing counterparts, CEM/ADR5000 and Lucena 1
The ethanol extracts obtained from Aldama tucumanensis, Ambrosia elatior, Baccharis artemisioides, Baccharis coridifolia, Dimerostemma aspilioides, Gaillardia megapotamica, and Vernonanthura nudiflora inhibited proliferation by 93–100% in acute lymphoblastic leukemia (ALL) cell lines while 70–90% inhibition was observed in the chronic myelogenous leukemia (CML) cells (Table 1)
Summary
Leukemia is a malignant disorder with a significant number of deaths annually [1]. According to GLOBOCAN, about 352,000 new cases of leukemia and 265,000 deaths occurred worldwide in 2012 [2].Despite overall improvement in the outcome of conventional leukemia therapies [3, 4], some patients have poor survival rates [5] or suffer from side effects of the drugs administered [3, 4, 6], and relapse is often observed [7]. Many cancers, including leukemia, are resistant to a wide array of chemically and functionally unrelated agents, a phenomenon known as multidrug resistance (MDR) Various mechanisms underlie this type of resistance, the most common being overexpression of the P-glycoprotein (Pgp) transporter (ABCB1/MDR1) [8]. More than a third of cells from patients with leukemia were positive to P-gp [10] High levels of this pump were detected in about 50% of patients with chronic myelogenous leukemia (CML) unresponsive to chemotherapy [11], while 12 and 29% of patients with acute myeloid leukemia (AML) showed high and intermediate P-gp expression, respectively [12]. Academy and industry still concentrate on finding promising candidates for an effective and safe therapy for leukemia
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