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

[Immanuel kant]

Perhaps Pentoxifylline may have a use for ridding the body pf senecent
cells in a combinational pharmacological approach. PS is a recognition
ligand in erythrocytes and immune cells anyway for removal.


BMC Cancer. 2011 Nov 10;11:483.

Pentoxifylline sensitizes human cervical tumor cells to cisplatin-
induced apoptosis by suppressing NF-kappa B and decreased cell
senescence.
Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-
Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, de Celis-
Carrillo R, del Toro-Arreola S, Castellanos-Esparza YC, Bravo-Cuellar
A.
SourceDivisión de Inmunología, Centro de Investigación Biomédica de
Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco,
México.

Abstract
BACKGROUND: Worldwide, 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.

METHODS: HeLa (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.

RESULTS: Our 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.

CONCLUSION: PTX 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.

PMID: 22074157 [PubMed - indexed