Molecular iodine inhibits the expression of stemness markers on cancer stem-like cells of established cell lines derived from cervical cancer

Abstract

BackgroundCancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Targeting CSC will provide novel treatments for cancer. Different investigations have focused on developing complementary approaches that involve natural compounds that decrease chemo-resistance and reduce the side effects of conventional therapies. Since, it has been reported that molecular iodine (I2) exhibits antineoplastic effects and decreases tumor progression in some cancer models, we evaluated the potential effect of I2 on cell cultures enriched in cervical cancer stem-like cells.MethodsHeLa and SiHa cervical cancer cells were treated with 200uM I2 for 24 h. After time, cells were cultured in CSC-conditioned medium (cervospheres) and viability assays were performed. Following, tumorigenic capabilities in cervospheres treated with I2 were evaluated in NOD/SCID mice. HeLa monolayer cells untreated and their respective cervosphere cells treated or untreated with 200 μM of I2 for 24 h were xenotransplanted subcutaneously at different amounts and mice were monitored for at least 2 months.ResultsIn the present study, monolayer and CSC-enriched cultures (cervospheres) from cervical cancer-derived cell lines, HeLa and SiHa, showed that 200uM I2 supplementation inhibits proliferation of both and decreased their tumorigenic capacity, in vivo. This antineoplastic effect of I2 was accompanied by diminished expression of stemness markers including CD49f, CK17, OCT-4, NANOG, SOX2, and KLF4, as well as increased expression and activation of PPARγ receptors.ConclusionsAll this data led us to suggest a clinical potential use of I2 for targeting CSC and improve current treatments against cervical cancer.

Targeting cancer stem cell pathways for cancer therapy

“…389 The PPARγ/NF-κB pathway promotes M2 polarization of macrophages to prevent cell death in ovarian CSCs 4.390 PPARγ activation promotes expression of its target gene PTEN to inhibit PI3K/Akt/ mTOR signaling, which stunts self-renewal, tumorigenicity, and metastasis in cervical CSCs, glioblastoma stem cells, and liver CSCs. 391,392 However, combined expression of Dnmt3a and Dnmt3b inhibits PPARγ expression by direct methylation of its promoter in squamous carcinomas. 393 PPARs are also closely related to the metabolism of CSCs.…”

Molecular Iodine Has Extrathyroidal Effects as an Antioxidant, Differentiator, and Immunomodulator

“…Similar results were obtained in trophoblast cells exposed to iodine supplementation increasing the synthesis of chorionic gonadotropin [ 84 ]. Moreover, studies related to stemness markers in breast and cervical cancer cells indicated that I 2 supplementation decreased the stem cell-like population, transforming the survival cells into non-invasive type cells incapable of generating xenografts [ 85 , 86 ]. In both conditions PPARγ receptors were increased.…”

Pterostilbene Suppresses both Cancer Cells and Cancer Stem-Like Cells in Cervical Cancer with Superior Bioavailability to Resveratrol

“…The stemness supporting transcription factors, such as Sox2, Klf4, c-Myc, Oct4, and Nanog, are upregulated in various types of CSCs [22,23,[26][27][28]. Our results demonstrated that pterostilbene effectively decreased the expression levels of the major stemness transcription factors, including Sox2, Oct4, and Nanog, as well as a cell surface marker for CSCs, CD133, suggesting that the inhibitory effect of pterostilbene against cervical CSCs may be associated with the downregulation of these stemness regulators.…”

“…To explore the mechanism by which resveratrol and pterostilbene inhibit the growth and migration of cervical CSCs, their effects on the expression of transcription factors, Sox2, Oct4, and Nanog, were investigated. These transcription factors have been reported to induce stem-like properties, in HeLa cancer stem-like cells [26][27][28]. The two compounds effectively reduced the expression levels of the key stemness-related transcription factors as well as CD133, a cell surface marker for CSCs, suggesting that the inhibitory effects of resveratrol and pterostilbene against cervical CSCs may be associated with the downregulation of these stemness regulators ( Figure 8A).…”