thiourea and Uterine-Cervical-Neoplasms

Looking for novel, effective and less toxic therapies for cervical cancer is of significant importance. In this study, we reported that HMQ-T-F2(F2) significantly inhibited cell proliferation and transplantable tumour growth. Mechanistically, HMQ-T-F2 inhibited HeLa cell growth through repressing the expression and nuclear translocation of β-catenin, enhancing Axin expression, as well as downregulating the Wnt downstream targeted proteins. Knock-down of a checkpoint β-catenin by siRNA significantly attenuated HeLa cell proliferation. Furthermore, XAV939, an inhibitor of β-catenin, was used to treat HeLa cells and the results demonstrated that HMQ-T-F2 inhibited proliferation and migration via the inhibition of the Wnt/β-catenin pathway.

Topics: Animals; Axin Protein; beta Catenin; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Mice; Thiourea; Transcriptional Activation; Up-Regulation; Uterine Cervical Neoplasms

Sarsasapogenin is a sapogenin from the Chinese medical herb Anemarrhena asphodeloides Bunge. In the present study, we revealed that sarsasapogenin exhibited antitumor activity by inducing apoptosis in vitro as determined by Hoechst staining analysis and double staining of Annexin V-FITC/PI. In addition, cell cycle arrest in G2/M phase was observed in sarsasapogenin-treated HeLa cells. Moreover, the results revealed that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio which led to the upregulation of cytochrome c, followed by activation of caspases. Meanwhile, treatment of sarsasapogenin also activated Unfolded Protein Response (UPR) signaling pathways and these changes were accompanied by increased expression of CHOP. Salubrinal (Sal), a selective inhibitor of endoplasmic reticulum (ER) stress, partially abrogated the sarsasapogenin-related cell death. Furthermore, sarsasapogenin provoked the generation of reactive oxygen species, while the antioxidant N-acetyl cysteine (NAC) effectively blocked the activation of ER stress and apoptosis, suggesting that sarsasapogenin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways. Taken together, the results demonstrate that sarsasapogenin exerts its antitumor activity through both reactive oxygen species (ROS)-mediate mitochondrial dysfunction and ER stress cell death.

Topics: Anemarrhena; Antineoplastic Agents; bcl-2-Associated X Protein; Cell Cycle Checkpoints; Cinnamates; Cytochromes c; Drugs, Chinese Herbal; Endoplasmic Reticulum Stress; Female; G1 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; M Phase Cell Cycle Checkpoints; Mitochondria; Mitochondrial Membranes; Reactive Oxygen Species; Spirostans; Thiourea; Transcription Factor CHOP; Unfolded Protein Response; Uterine Cervical Neoplasms

The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromans; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred Strains; Ovarian Neoplasms; Phenylurea Compounds; Receptors, Retinoic Acid; Retinoid X Receptors; RNA; Skin Irritancy Tests; Thiones; Thiourea; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays