Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence
Open Access
- 19 May 2010
- journal article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 9 (1), 114
- https://doi.org/10.1186/1476-4598-9-114
Abstract
Background: Chemotherapeutic drugs like Adriamycin (ADR) induces apoptosis or senescence in cancer cells but these cells often develop resistance and generate responses of short duration or complete failure. The methylxantine drug Pentoxifylline (PTX) used routinely in the clinics setting for circulatory diseases has been recently described to have antitumor properties. We evaluated whether pretreatment with PTX modifies apoptosis and senescence induced by ADR in cervix cancer cells. Methods: HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, ADR or PTX + ADR. The cellular toxicity of PTX and survival fraction were determinated by WST-1 and clonogenic assay respectively. Apoptosis, caspase activation and ADR efflux rate were measured by flow cytometry, senescence by microscopy. IκBα and DNA fragmentation were determinated by ELISA. Proapoptotic, antiapoptotic and senescence genes, as well as HPV-E6/E7 mRNA expression, were detected by time real RT-PCR. p53 protein levels were assayed by Western blot. Results: PTX is toxic (WST-1), affects survival (clonogenic assay) and induces apoptosis in cervix cancer cells. Additionally, the combination of this drug with ADR diminished the survival fraction and significantly increased apoptosis of HeLa and SiHa cervix cancer cells. Treatments were less effective in HaCaT cells. We found caspase participation in the induction of apoptosis by PTX, ADR or its combination. Surprisingly, in spite of the antitumor activity displayed by PTX, our results indicate that methylxantine, per se does not induce senescence; however it inhibits senescence induced by ADR and at the same time increases apoptosis. PTX elevates IκBα levels. Such sensitization is achieved through the up-regulation of proapoptotic factors such as caspase and bcl family gene expression. PTX and PTX + ADR also decrease E6 and E7 expression in SiHa cells, but not in HeLa cells. p53 was detected only in SiHa cells treated with ADR. Conclusion: PTX is a good inducer of apoptosis but does not induce senescence. Furthermore, PTX reduced the ADR-induced senescence and increased apoptosis in cervix cancer cells.This publication has 41 references indexed in Scilit:
- The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-κB Activation and Confers a Worse Prognosis in GlioblastomaCancer Research, 2009
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesionsBMC Cancer, 2008
- Diagnosis and management of cervical cancerBMJ, 2007
- Apoptosis: A Review of Programmed Cell DeathToxicologic Pathology, 2007
- Senescence As an Anticancer MechanismJournal of Clinical Oncology, 2007
- In vivo and in vitro sensitization of leukemic cells to adriamycin-induced apoptosis by pentoxifylline: Involvement of caspase cascades and IκBα phosphorylationImmunology Letters, 2006
- Src Inhibits Adriamycin-Induced Senescence and G2 Checkpoint Arrest by Blocking the Induction of p21waf1Cancer Research, 2005
- Restoration of p53 expression sensitizes human papillomavirus type 16 immortalized human keratinocytes to CD95-mediated apoptosisOncogene, 2002
- Cellular senescence as a tumor-suppressor mechanismTrends in Cell Biology, 2001