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Junín de los Andes, Argentina

Vazquez R.,CONICET | Riveiro M.E.,CONICET | Mondillo C.,CONICET | Perazzo J.C.,Laboratorio Of Hipertension Portal Y Encefalopatia Hepatica | And 4 more authors.
Biochemical Pharmacology | Year: 2013

The development of tumor-selective drugs with low systemic toxicity has always been a major challenge in cancer treatment. Our group previously identified the 7,8-dihydroxy-4-methylcoumarin (DHMC) as a potential chemotherapeutic agent due to its potent, selective anti-proliferative and apoptosis-inducing effects on several cancer cell lines over peripheral blood mononuclear cells. However, there are still no published reports that can explain such selectivity of action. Herein, we addressed this question by using the U-937 promonocytic leukemia cell line, which can be forced to differentiate into a monocyte-like phenotype in vitro. U-937 cells differentiation is dependent on the nuclear expression of p21Cip1/WAF1, a protein that is absent in immature U-937 cells but present in both the nucleus and the cytoplasm of normal DHMC-resistant monocytes. Considering that induction of differentiation rendered U-937 cells resistant to DHMC, we evaluated the possible causal role of cytoplasmic p21Cip1/WAF1 in the onset of such resistance by employing U-937 cells stably transfected with a ZnCl2-inducible p21Cip1/WAF1 variant lacking the nuclear localization signal (U-937/CB6-DNLS-p21 cells). Expression of cytoplasmic p21Cip1/ WAF1 did not induce differentiation of the cells but turned them resistant to DHMC through inhibition of JNK, a crucial mediator of DHMC-induced apoptosis in U-937 cells. Sub-acute toxicity evaluation of DHMC in Balb/c mice indicated that DHMC administered intraperitoneally at doses up to 100 mg/kg induced no systemic damage. Collectively, our results explain for the first time the selective cytotoxicity of DHMC for tumor cells over normal monocytes, and encourage further in vivo studies on this compound as potential anti-leukemic agent. © 2013 Elsevier Inc. All rights reserved.

Vazquez R.,CONICET | Riveiro M.E.,CONICET | Vermeulen M.,Institute Investigaciones Hematologicas | Alonso E.,Catedra de Quimica Medicinal | And 9 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Previous studies indicated the need of at least one phenolic hydroxyl group in the coumarin core for induction of cytotoxicity in different cell lines. Herein, we present an exhaustive structure-activity relationship study including ortho-dihydroxycoumarins (o-DHC) derivatives, cinnamic acid derivatives (as open-chain coumarin analogues) and 1,2-pyrones (representative of the δ-lactone ring of the coumarin core), carried out to further identify the structural features of o-DHC required to induce leukemic cell differentiation and apoptosis in U-937 cells. Our results show for the first time that the δ-lactone ring positively influences the aforementioned biological effects, by conferring greater potency to compounds with an intact coumarin nucleus. Most tellingly, we reveal herein the crucial role of this molecular portion in determining the selective toxicity that o-DHC show for leukemic cells over normal blood cells. From a pharmacological perspective, our findings point out that o-DHC may be useful prototypes for the development of novel chemotherapeutic agents. © 2011 Elsevier Ltd. All rights reserved.

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