Enhanced antiproliferative effects of alkoxyalkyl esters of cidofovir in human cervical cancer cells in vitro

Abstract

Nearly all cervical cancers are associated with the high-risk subtypes of human papillomavirus (HPV) expressing the E6 and E7 oncoproteins. The E6 and E7 oncoproteins reduce cellular levels of the p53 and the retinoblastoma (pRb) tumor suppressors, respectively, and represent an important component of the malignant phenotype. Several groups have shown that treatment with cidofovir suppresses levels of E6 and E7, restoring cellular p53 and pRb levels, in turn slowing cell replication and increasing the susceptibility of the cancer cells to radiation and apoptosis. Recently, our group synthesized alkoxyalkyl esters of cidofovir, which were found to be >100 times more active than unmodified cidofovir in vitro against various doublestranded DNA viruses, including cytomegalovirus, herpes simplex virus, adenoviruses, cowpox, vaccinia, and variola viruses. We compared the activity of octadecyloxyethylcidofovir (ODE-CDV) and oleyloxyethyl-cidofovir (OLE-CDV) with that of unmodified cidofovir against both HPV-negative and HPV-positive cervical cancer cells. We compared the antiproliferation activity in CaSki, HeLa, and Me-180 cells, prototypical HPV-positive cell lines bearing the HPV-16, HPV-18, and HPV-68 high-risk subtypes, with the activity in C33A cells, a cervical cancer cell line lacking HPV, and in nonmalignant primary human foreskin fibroblast cells. OLE-CDV and ODE-CDV were several logs more potent than cidofovir in CaSki, Me-180, HeLa, and C33A cervical cancer cells as determined by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H -tetrazolium-5-carboxanilide inner salt proliferation assay. Cell cycle analysis indicates that the cidofovir analogues interfere with passage of dividing cells through the S phase. ODE-CDV and OLE-CDV were 500 to 17,000 times more active than cidofovir in inhibiting the growth of cervical cancer cells. ODE-CDV and OLE-CDV showed selectivity for cervical cancer cells versus nonmalignant human foreskin fibroblast cells and warrant further investigation as potential therapies for cervical cancer. [Mol Cancer Ther 2006; 5(1):156-9]

Inhibitory Activities of Three Classes of Acyclic Nucleoside Phosphonates against Murine Polyomavirus and Primate Simian Virus 40 Strains

“…In order to increase the cellular uptake and oral bioavailability of HPMPC, several alkoxyalkyl esters have been designed. These compounds proved to be highly active and selective against adenovirus, poxviruses, human papillomavirus, cytomegalovirus, and herpes simplex virus (3,7,9,15,23). When these prodrugs were given orally to treat cowpox and vaccinia virus infections in mice, they were as active as HPMPC given parenterally (18).…”

The Octadecyloxyethyl Ester of ( S )-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons

“…The selectivity indices for the current compounds are moderate, in the range of 20 to 40, but encouraging for lead compounds. It should be kept in mind that the cytotoxicity testing was only performed in Huh-7.5.1 cells, a liver cancer cell line, which may be more prone to the antiproliferative effects of nucleosides than are primary hepatocytes or non-tumor-based cell lines (11). In HCV RNA assay results of genotype 1A and 1B replicons, ODE-(S)-HPMPA was active with EC 50 values of 1.8 Ϯ 0.3 and 2.1 Ϯ 0.2 M, similar to those observed in genotypes 1B and 2A with the luciferase assay ( Table 1).…”

Antiproliferative Effects of Octadecyloxyethyl 9-[2-(Phosphonomethoxy)Ethyl]Guanine against Me-180 Human Cervical Cancer Cells in vitro and in vivo

“…The acyclic nucleoside phosphonate (S)-1-[3-hydroxy-2-(phosphonylmethoxy)-propyl]-cytosine (cidofovir, CDV) has been reported to selectively inhibit the proliferation of human papillomavirus DNA+ cancer cells in vitro [1][2][3][4][5] , in animals [2] and in men [6] . CDV is reported to reduce levels of the E6 oncoprotein resulting in an increase in p53 and pRb, allowing the cell to regain control of the cell cycle, slowing proliferation and leading to apoptosis [2][3][4] .…”

“…Similar results were noted with HDP esters of (S)-HPMPA in HIV-1-infected cells [12][13][14] . As noted above, CDV has been reported to be strongly antiproliferative against cervical cancer cells [1][2][3][4][5] . We studied the effect of ODE-CDV and several other CDV analogs on the proliferation of primary fibroblast and human cervi- 55 cal cancer cell lines in vitro.…”

“…We studied the effect of ODE-CDV and several other CDV analogs on the proliferation of primary fibroblast and human cervi- 55 cal cancer cell lines in vitro. ODE-CDV was several logs more active in inhibiting proliferation of cervical cancer cells than CDV and showed 2.5-to 140-fold selectivity for cervical cancer cells versus normal human foreskin fibroblast (HFF) cells [1] .…”