In vivo and in vitro sensitization of leukemic cells to adriamycin-induced apoptosis by pentoxifyllineInvolvement of caspase cascades and IκBα phosphorylation

Lerma-Díaz, José Manuel; Hernández‐Flores, Georgina; Domínguez-Rodríguez, Jorge Ramiro; Ortiz‐Lazareno, Pablo César; Gomez-Contreras, Piedad C.; Cervantes-Munguía, Ramón; Scott‐Algara, Daniel; Aguilar‐Lemarroy, Adriana; Jave‐Suárez, Luis Felipe; Bravo-Cuéllar, Alejandro

doi:10.1016/j.imlet.2005.10.019

Cited by 29 publications

(32 citation statements)

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“…In this respect, our group reported that the 100% of lymphoma-bearing mice treated with PTX + adriamycin, an anthracycline, survived for > 1 year after receiving only one half of the therapeutic dosage of adriamycin. Similarly, we also observed that PTX increased the levels of apoptosis generated by adriamycin in fresh leukemic cells of pediatric patients [12-14]. Sensitization of tumor cells to adriamycin by PTX is not tumor type specific.…”

Section: Introductionmentioning

confidence: 63%

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

et al. 2011

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BackgroundWorldwide, cervical cancer is the second most common causes of cancer in women and represents an important mortality rate. Cisplatin (CIS) is a very important antitumoral agent and can lead tumor cells toward two important cellular states: apoptosis and senescence. In some types of cancers pentoxifylline (PTX) sensitizes these cells to the toxic action of chemotherapeutics drugs such as adriamycin, inducing apoptosis. In the present work, we studied in vitro whether PTX alone or in combination with CIS induces apoptosis and/or senescence in cervix cancer HeLa and SiHa cell lines infected with HPV types 16 and 18, respectively, as well as in immortalized keratinocytyes HaCaT cells.MethodsHeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, CIS or both. The cellular toxicity and survival fraction of PTX and CIS were determinate by WST-1 and clonogenic assays respectively. Apoptosis, caspase activation and phosphorylation of ERK1/2, p38, p65 (NF-κB), Bcl-2 and Bcl-XL anti-apoptotic proteins were determinated by flow cytometry. Senescence by microscopy. Phosphorylation of IκBα and IκB total were measured by ELISA. Pro-apoptotic, anti-apoptotic and senescence genes, as well as HPV-E6/7 mRNA expression, were detected by RT-PCR.ResultsOur results show that after 24 hours of incubation PTX per se is toxic for cancer cells affecting cell viability and inducing apoptosis. The toxicity in HaCaT cells was minimal. CIS induces apoptosis in HeLa and SiHa cells and its effect was significantly increases when the cells were treated with PTX + CIS. In all studies there was a direct correlation with levels of caspases (-3, -6, -7, -9 and -8) activity and apoptosis. CIS induces important levels of senescence and phosphorylation of ERK1/2, p38, p65/RELA, and IκBα, and decreased the expression of anti-apoptotic protein Bcl-XL. Surprisingly these levels were significantly reduced by PTX in tumor cells, and at the same time, increases the expression of pro-apoptotic genes.ConclusionPTX sensitizes cervical cancer cells to CIS-induced apoptosis and decreases the CIS-induced senescence in these cells via inhibition of NF-κB signaling pathway; diminishes expression of antiapoptotic proteins and the activation of caspases.

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Section: Introductionmentioning

confidence: 63%

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

et al. 2011

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“…It is well known that apoptosis represents an important physiological pathway of cell death other than one of the possible main modalities of cell death after chemotherapy, the other one being necrosis. As many other anticancer drugs, doxorubicin is able to trigger apoptosis in tumor and normal tissues both in vitro and in vivo [36][37][38]. This is the reason why we decided to study this important mechanism of cell death in vitro when the topoisomerase inhibitor was co-administered together with the tested nifedipine or diltiazem-like compounds.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

et al. 2009

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We report herein the reversal of multidrug resistance-1 (MDR1) in A2780/DX3 cells by the two nifedipine-like compounds 1 and 2 that are part of a library of 1,4-dihydropyridines (1,4-DHPs) calcium-channel modulators bearing in C-4 a different substituted imidazo[2,1-b]thiazole system. By methylthiazol tetrazolium (MTT) assay, cytofluorimetry, and fluorescence microscopy we evaluated their ability to reverse MDR in our cell system. Moreover, together with compound 3 (the diltiazem-like 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one) we analyzed their ability to potentiate the triggering of apoptosis after exposure to doxorubicin, through the nuclear morphological analysis after 4',6-diamidino-2-phenylindole (DAPI), the fluorescein isothiocyanate (FITC)-Annexin-V/propidium iodide (PI) staining and the caspase activity determination. Our results demonstrate that compounds 1 and 2, at concentrations showing a very low (5%) or absent inhibition of cell proliferation, in combination with doxorubicin enhance its antiproliferative activity (from 30% to 54% IC(50) reduction) in A2780/DX3 cells through an increase of doxorubicin intracellular accumulation. These compounds together with compound 3, which has already been demonstrated to act as a potent inhibitor of MDR1 function, were also able to significantly potentiate the activation of the apoptosis machinery triggered by the exposure to doxorubicin. In conclusion, our results identify two new molecules structurally related to the calcium-channel blocker nifedipine, but characterized by a very low LTCC blockers activity, able to potentiate the antiproliferative and apoptotic activities of doxorubicin through an increase of its intracellular concentration likely caused by the inhibition of MDR1 function.

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“…La PTX a déjà été largement utilisée en routine en clinique dans le traitement des maladies vasculaires depuis plus de vingt ans [2,3]. Expérimentalement, nous avons observé que 100 % des souris porteuses du lymphome L5178Y traitées par l'association PTX + adriamycine (ADR) survivent plus d'un an, alors même qu'elles n'avaient reçu que la moitié d'une dose d'ADR qui génère 40 % de survie des animaux [4]. La PTX peut également augmenter l'expression des protéines pro-apoptotiques BCL-2 comme BAX par les cellules U937 en culture chez lesquelles l'apoptose est induite par l'alcool périllyque [5].…”

Section: In Vitro Induction Of Apoptosis In Acute Myelogenous and Lymunclassified

“…L'étude a été approuvée par le Comité d'Éthique du Centro de Investigación Biomédica de Occidente del IMSS. Dans des plaques Costar (12 trous), 10 6 leucoblastes leucémi-ques de sang périphérique ont été mis en suspension dans 1 mL de milieu de culture RMPI-1640 additionné de 10 % du sérum bovin foetal, de L-glutamine ( [4]. Les résultats sont la moyenne AE déviation standard.…”

Section: Matériel Et Méthodesunclassified

L’apoptose de cellules de leucémie aiguë myéloblastique et lymphoblastique, induite in vitro par l’adriamycine, est augmentée par la pentoxifylline

et al. 2010

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In vivo and in vitro sensitization of leukemic cells to adriamycin-induced apoptosis by pentoxifyllineInvolvement of caspase cascades and IκBα phosphorylation

Cited by 29 publications

References 54 publications

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

Inhibition of MDR1 activity and induction of apoptosis by analogues of nifedipine and diltiazem: an in vitro analysis

L’apoptose de cellules de leucémie aiguë myéloblastique et lymphoblastique, induite in vitro par l’adriamycine, est augmentée par la pentoxifylline

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