Human Cervix Cancer Research Articles

Development of New 5‐(Oxazol‐2‐yl)Pyrimidine Derivatives with Promising Anticancer Activities

AbstractA novel series of oxazolyl‐pyrimidine derivatives (11 a–j) have been synthesized and structures were confirmed by spectral data. The synthesized compounds were assessed for cytotoxic profile towards human cervix cancer (SiHa), lung cancer (A549), breast cancer (MCF‐7), and colon cancer (Colo‐205) cell lines by employing MTT assay and using etoposide as the positive control. The heteroaryl compounds having the terminal pyridyl (11 a) and thiazolyl (11 b) groups showed superior cytotoxic potency against cervix and lung cancer cell lines and varying methoxy substituted derivatives 11 c–11 e have excellent to good cytotoxic properties. Compound 11 a and 11 b have IC50 values in the range of 0.01±0.0034 to 0.17±0.059 μM and 0.10±0.038 to 0.66±0.077 μM respectively in the tested cell lines. The selected compounds 11 a and 11 b were studied by molecular docking to assess the binding interactions, binding energies, and possible mechanisms. The in‐silico ADME properties were calculated and all the compounds have the desired properties of drug‐like molecules. The toxicity results indicate that all the compounds are free from toxicity except 11 j, which has high tumorigenic properties. The optimized structure, energies of frontier molecular orbitals, molecular electrostatic potential, and NLO parameters for compound 11 a were determined using DFT/B3LYP level with a 6‐311++G(d,p) basis set.

Calix[4]pyrrole‐Grafted Gold Nanoparticles as a Turn‐On Fluorescence Sensor for Noxious Fungicide Dimoxystrobin and Their Anti‐Cancer Activity against the KB‐3‐1 Cell Line

AbstractA rapid and easy approach for producing very stable gold nanoparticles has been discovered. Calix[4]pyrrole tetrahydrazide (CPTAH) was utilized effectively in the synthesis of gold nanoparticles as a reducing and stabilizing agent. These functionalized AuNPs were characterized by Surface Plasmon Resonance, Transmission Electron Microscopy, Selected Area Electron Diffraction, and Energy Dispersive X‐ray techniques. CPTAH‐AuNPs possessed a particle size of 11±2 nm and are highly stable at pH 7.0 for more than 150 days. The selectivity and sensitivity of CPTAH‐AuNPs as a fungicide sensor was assessed for Metalaxyl, Mancozeb, Tebuconazole, Tricyclozole, Dimoxystrobin, Kresoxim‐methyl, and Carbendazim, amongst which Dimoxystrobin (DMX) was sensed exclusively with naked eyes by means of aggregation of CPTAH‐AuNPs with a detection limit of the order of 5 ppm using “Turn‐on” fluorescence enhancement. Additionally, the CPTAH‐AuNPs were found to be effective cytotoxic agent against the human cervix cancer cell line KB‐3‐1 with IC50 value of 64.63 μg/mL which admits the employability of CPTAH‐AuNPs in the study of development of anti‐cancer drug.

Novel Peptide from the Hydrolysate of Hybrid Sturgeon (Acipenseridae) Spinal Cord: Isolation, Identification, and Anti-proliferative Effects in Human Cervix Cancer Cells.

Anti-proliferative peptides have recently attracted attention for their excellent bioactivity and biocompatibility. In this paper, five novel anti-proliferative peptides were identified from the hydrolysate of hybrid sturgeon spinal cord (HSSC). In addition, the structure-activity relationship of the novel anti-proliferative peptides was explored. In vitro experiments indicated that the peptide "VDSVLDVVRK" presented the highest inhibition of HeLa cell growth in all samples (IC50 = 2.5 μM). VDSVLDVVRK showed a random coil secondary structure and nanomicelles in the tumor microenvironment. Transmission electron microscopy results confirmed that nanomicelles disassemble as the concentration of VDSVLDVVRK decreases. Furthermore, VDSVLDVVRK could induce HeLa cell apoptosis by increasing the expression of Cyt-c (98.65 ± 1.85%, p < 0.01) and caspase-9 (39.85 ± 1.81%, p < 0.01). In this study, the anti-proliferative mechanism of the HSSC peptide was discussed, which provided a theoretical basis for the research and development of anti-proliferative functional food.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

In Vitro Cytotoxic Activity of Total Flavonoid from Equisetum Arvense Extract.

Normally happening substances like flavonoids are regarded as active candidates for the treatment and prevention of cancer The purpose of this study was to see how Iraqi E. arvense total flavonoid affected cell lines biologically and human lung fibroblast normal cell line (WISH). Plant powder was extracted by reflex apparatus, then thin-layer chromatography (TLC) was used to determine total flavonoids. Cytotoxicity assay (MTT) was used to determine the cytotoxic activity of the prepared plant against human breast cancer (MCF-7), cells human cervix cancer (HELA), human colon cancer (Caco-2) and human lung fibroblast normal cell line (WISH). The flavonoids Rutin, Quercetin, Kaempferol, and luteolin were detected using the Thin Layer Chromatography (TLC) technique. In contrast to the negative control, the extract inhibited cell growth to a highest of 82.158% for MCF-7 and 61.360% for Caco-2 at the concentration (100 µg/ml), and (54.880%) for Hela cell line at the concentration (100 µg/ml). In addition, the concentration (6.25 µg/ml) of total flavonoid extract produced a decrease in the growth of the normal WISH cell line to reach (1.094%). Equisetum arvense contain high amounts of flavonoids, the qualification of some flavonoids compounds was detected using TLC. The total flavonoids showed significant cytotoxic activity against various types of cancer cell lines and normal cell line in vitro, the antitumor activity was highly efficient in a dose and cell type dependent manner.

High expression level of CXCL1/GROα is linked to advanced stage and worse survival in uterine cervical cancer and facilitates tumor cell malignant processes

BackgroundCXCL1 belongs to a member of the ELR + CXC chemokine subgroups that also known as GRO-alpha. It has been recognized that several types of human cancers constitutively express CXCL1, which may serve as a crucial mediator involved in cancer development and metastasis via an autocrine and/or paracrine fashion. However, the expression pattern and clinical significance of CXCL1 in human uterine cervix cancer (UCC), as well as its roles and mechanisms in UCC tumor biology remains entirely unclear.MethodsThe expression and clinical significance of CXCL1 in UCC tissues was explored using immunohistochemistry and bioinformatics analyses. The expression and effects of CXCL1 in HeLa UCC cells were assessed using ELISA, CCK-8 and transwell assays. Western blotting experiments were performed to evaluate the potential mechanism of CXCL1 on malignant behaviors of HeLa UCC cells.ResultsThe current study demonstrated that CXCL1 was expressed in HeLa UCC cells, PHM1-41 human immortalized cervical stromal cells, as well as cervical tissues, with UCC tissues having an evidently high level of CXCL1. This high level of CXCL1 in cancer tissues was notably related to poor clinical stages and worse survival probability, rather than tumor infiltration and patient age. In addition, CXCL1 expression was extremely correlated with CCL20, CXCL8 and CXCL3 cancer-associated chemokines expression. In vitro, the growth and migration abilities of HeLa cells were significantly enhanced in the presence of exogenous CXCL1. Gain-function assay revealed that CXCL1 overexpression significantly promoted growth and migration response in HeLa cells in both autocrine and paracrine manners. Finally, we found that CXCL1 overexpression in HeLa cells influenced the expression of ERK signal-related genes, and HeLa cell malignant behaviors derived from CXCL1 overexpression were further interrupted in the presence of the ERK1/2 blocker.ConclusionOur findings demonstrate the potential roles of CXCL1 as a promoter and a novel understanding of the functional relationship between CXCL1 and the ERK signaling pathway in UCC.

Integration of in vitro and in silico approaches to assess three Astragalus species from Turkey flora: A novel spotlight from lab bench to functional applications

Members of the genus Astragalus have a great interest as a source of natural bioactive compounds on a scientific platform. To provide multidirectional insights into three Astragalus species (A. setulosus, A. anthylloides, and A. ovalis), the current work focused on the chemical characterization and biological properties of their extracts (aerial parts and roots). The chemical characterization of the extracts was detected by HPLC-MS/MS analysis. The biological properties were evaluated by antioxidant, enzyme inhibitory, and cytotoxic parameters. Assays for radical quenching, reducing capacity, and metal chelation were also used to evaluate antioxidant properties. To test the enzyme inhibitory effects of the extracts, cholinesterases, tyrosinase, α-amylase, and α-glucosidase were utilized as target enzymes. Two cancer cell lines, (MCF-7 (human breast cancer cell line) and HeLa (Human cervix cancer cell line), were selected to evaluate cytotoxic effects. Generally, 5- caffeoylquinic acid (2.43–283.92 μg/g extract), hyperoside (4.33–216.22 μg/g extract) and rutin (1.09–184.98 μg/g extract) were the main constituents. The extracts from aerial parts and roots of A. anthylloides showed stronger radical scavenging and reducing power abilities compared to A. setulosus and A. ovalis. The best AChE and BChE inhibitory effects were determined in the aerial parts of A. setulosus (2.18 mg GALAE/g) and roots of A. ovalis (4.76 mg GALAE/g), respectively. The extracts of A. ovalis had the highest tyrosinase inhibitory abilities. The extract from aerial parts of A. setulosus showed stronger cytotoxic effects compared to other extracts. Pearson's correlation analysis revealed that the presence of some compounds (resveratrol, p-coumaric, 5-caffeoylquinic, and ferulic acids, etc) was linked to the observed biological activities. Molecular docking was also provided for the possible interaction of enzymes as well as protein targets of the tested cell lines. Our findings provide a scientific basis for the Astragalus species, which may serve as a source of naturally occurring bioactive compounds for health-promoting applications.

Design, synthesis, and biological evaluation of chalcone based derivatives of 1,3,4-thiadazole-oxazole as cytotoxic agents

A new series of chalcone incorporated 1,3,4-thiadazole-oxazole (10a-j) compounds have been prepared and its chemical structures were confirmed by spectroscopic techniques. Further, all compounds were explored for cytotoxic properties alongside human cervix cancer (SiHa), human lung cancer (A549), human breast cancer (MCF-7) and human colon cancer (Colo-205) cell lines by employing MTT assay. The known chemotherapeutic drug candidate as etoposide used as positive control. According to the data, all the compounds showed good to moderate activities. Among them, compounds 10a, 10b, 10c and 10d displayed most promising activity.

Anticancer effect of Citrullus colocynthis and Capparis spinosa against human Cervix and Hepatocellular cancer cell lines

Anticancer effect of Citrullus colocynthis and Capparis spinosa against human Cervix and Hepatocellular cancer cell lines

Overexpression of Eukaryotic translation initiation factor 3D induces stem cell-like properties and metastasis in cervix cancer by activating FAK through inhibiting degradation of GRP78

ABSTRACT Cervix cancer (CC) is the most common gynecological malignancy and the leading cause of morbidity among women worldwide. Previous study indicated that cancer stem cells (CSCs) existed in cervix cancer, and suppressing CSC characteristics of cervix cancer is needed to combat this disease. Eukaryotic translation initiation factor 3 (EIF3) is one of the most complex eukaryotic translation initiation factors containing 13 subunits (EIF3A-EIF3M) and it regulates eukaryotic translation. One member of EIF3, EIF3D, plays a role in the progression and development of multiple tumors. However, its possible role in cervix cancer progression is still unclear. In this study, we found the high EIF3D expression in human cervix cancer tissues. We further found that downregulation of EIF3D suppressed the proliferation and motility of cervix cancer cells. Furthermore, its downregulation restrained the stem cell-like properties of cervix cancer cells. Mechanically, we found that EIF3D promoted FAK activation through GRP78 in cervix cancer cells, thus contributing to the progression of cervix cancer. Therefore our results suggested that EIF3D could serve as a promising target of cervix cancer.

Design, synthesis and biological evaluation of amide derivatives of oxazol-benzofuran-isoxazols as anticancer agents

A library of amide derivatives of oxazol-benzofuran-isoxazols ( 13a-j) have designed, synthesized and their structures were characterized by spectroscopic techniques. These compounds were investigated for in vitro anti-proliferative potential against human prostate cancer (PC3), human lung cancer (A549), human breast cancer (MCF-7) and human cervix cancer (SiHa) cancer cell lines by using of MTT asaay, and the etoposide used as standard reference. All compounds displayed remarkable anti-proliferative potential. Among them, compounds 13a, 13b, 13c and 13d showed most promising activities than etoposide. In which one of the compound 13c possessed superior activity. Further the structure-activity relationships (SARs) of these compounds were also examined.

Cytotoxic Effect of Biebersteinia multifida Alcoholic Extracts on MCF-7, HeLa, and A2780 Cell Lines.

Conventional cancer treatments are costly and have different serious side effects for patients. Natural herbal treatments are widely accepted among people because of their minimal side effects, although there is little scientific knowledge about them. One of these remedies utilizes the root of Biebersteinia multifidi that has been used for years in Iran to treat different chronic genital diseases. The current study examined the effects of methanolic and ethanolic extracts of B. multifida (induction of necrosis and apoptosis) on breast cancer (MCF-7), ovarian cancer (A2780), and human cervix cancer (HeLa) cell lines in comparison with normal breast cells. These effects were determined to be morphological alterations in cell light microscopy, by flow cytometry (staining with annexin V and propidium iodide), and by measuring live cells and inhibition concentrations by MTT assay. IC50 of B. multifida on the MCF-7 cell line (methanolic extract) was 400 µg/ml and for A2780 was 250 µg/ml. The IC50 amount of B. multifida on the MCF-7 cell line (ethanolic extract) was 750 µg/ml and 1500 for A2780. Results demonstrated that apoptosis and necrosis occurred in MCF-7 and A2780 following the addition of ethanolic and methanolic extracts of B. multifida to the medium. These findings confirmed the anti-cancer effects of mehthanolic extracts of Biebersteinia multifida root and its safety for normal cells; thus, it can be applied in cancer therapy as a novel medication.

Non-Steroidal Anti-Inflammatory Drugs Increase Cisplatin, Paclitaxel, and Doxorubicin Efficacy against Human Cervix Cancer Cells.

This study shows that the non-steroidal anti-inflammatory drug (NSAID) celecoxib and its non-cyclooxygenase-2 (COX2) analogue dimethylcelecoxib (DMC) exert a potent inhibitory effect on the growth of human cervix HeLa multi-cellular tumor spheroids (MCTS) when added either at the beginning (“preventive protocol”; IC50 = 1 ± 0.3 nM for celecoxib and 10 ± 2 nM for DMC) or after spheroid formation (“curative protocol”; IC50 = 7.5 ± 2 µM for celecoxib and 32 ± 10 µM for DMC). These NSAID IC50 values were significantly lower than those attained in bidimensional HeLa cells (IC50 = 55 ± 9 µM celecoxib and 48 ± 2 µM DMC) and bidimensional non-cancer cell cultures (3T3 fibroblasts and MCF-10A mammary gland cells with IC50 from 69 to >100 µM, after 24 h). The copper-based drug casiopeina II-gly showed similar potency against HeLa MCTS. Synergism analysis showed that celecoxib, DMC, and casiopeinaII-gly at sub-IC50 doses increased the potency of cisplatin, paclitaxel, and doxorubicin to hinder HeLa cell proliferation through a significant abolishment of oxidative phosphorylation in bidimensional cultures, with no apparent effect on non-cancer cells (therapeutic index >3.6). Similar results were attained with bidimensional human cervix cancer SiHa and human glioblastoma U373 cell cultures. In HeLa MCTS, celecoxib, DMC and casiopeina II-gly increased cisplatin toxicity by 41–85%. These observations indicated that celecoxib and DMC used as adjuvant therapy in combination with canonical anti-cancer drugs may provide more effective alternatives for cancer treatment.

Etanol ve Dimetil Sülfoksidin Çeşitli İnsan Hücre Hatları Üzerindeki in vitro Sitotoksik Etkisi

Although the cytotoxic effects of ethanol and dimethyl sulfoxide (DMSO) on some cell lines have been shown in the literature, there is no study about the cytotoxic effects of these solvents on common used human cell lines, such as melanoma (VMM917), lung cancer (A549), colon cancer (WiDr), normal colon (CCD 841 CoN) and fibroblast (BJ) cells. The aim of this study was to determine the cytotoxic effects of ethanol and DMSO on human breast (MCF-7), liver (HepG2) and cervix (HeLa) cancer cells in addition to above mentioned cells. For this purpose, the cells were treated with different concentrations (0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 2%, and 4%, v/v) of ethanol and DMSO and then subjected to MTT assay. According to the results, ethanol and DMSO exhibited dose-dependent cytotoxicity in all cells studied. The most DMSO and ethanol sensitive cells were WiDr and VMM917, while the most resistant cells were determined as BJ and A549, respectively. The results revealed that the concentration range in which ethanol and DMSO exhibited cytotoxic effect in each cell line is different. In order not to cause false positive and negative results, the concentration range in which the solvents used in cell culture studies do not have cytotoxic effects should be determined.

Tri N-Heterocyclic Carbene Trinuclear Silver(I) complexes: Synthesis and In Vitro cytotoxicity studies

Synthesis of ethylene linked tris benzimidazolium bromide salts that serve as precursors for the tri-NHC ligands in the respective tri-NHC trinuclear silver(I) complexes is described (NHC = N-heterocyclic carbene). Different wingtip substituents were selected (benzyl, n-butyl, cyclopentyl, 2-methylene benzonitrile, n-decyl) to furnish five new tris benzimidazolium salts (1-5) and the respective tri-NHC trinuclear silver(I) complexes (6-10). The synthesized and characterized compounds (1-10) were evaluated for their cytotoxic potential on human colon, human breast and human epitheloid cervix cancer cell lines by determining their IC50 values and evaluating their antiproliferative activity against the selected cell lines. The tested compounds were found to be good anticancer agents against breast cancer and cervical cancer cell lines and selectively good anticancer agents for the human colon cancer cell line.

An EPR Study Using Cyclic Hydroxylamines To Assess The Level of Mitochondrial ROS in Superinvasive Cancer Cells.

It has been proposed that a mitochondrial switch involving a high mitochondrial superoxide production is associated with cancer metastasis. We here report an EPR analysis of ROS production using cyclic hydroxylamines in superinvasive SiHa-F3 compared with less invasive SiHa wild-type human cervix cancer cells. Using the CMH probe, no significant difference was observed in the overall level of ROS between SiHa and SiHa-F3 cells. However, using mitochondria-targeted cyclic hydroxylamine probe mitoTEMPO-H, we detected a significantly higher mitochondrial ROS content in SiHa-F3 compared with the wild-type SiHa cells. To investigate the nature of mitochondrial ROS, we overexpressed superoxide dismutase 2, a SOD isoform exclusively localized in mitochondria, in SiHa-F3 superinvasive cells. A significantly lower signal was detected in SiHa-F3 cells overexpressing SOD2 compared with SiHa-F3. Despite some limitations discussed in the paper, our EPR results suggest that mitochondrial ROS (at least partly superoxide) are produced to a larger extent in superinvasive cancer cells compared with less invasive wild-type cancer cells.

Cytotoxic activity against breast cancer cells of two species of marine sponges from shallows of Yucatan peninsula

This study aimed to evaluate the in vitro activity of extracts of two marine sponge species, occurring in the shallows of the Yucatan peninsula coast, on two cancer and one normal mammalian cell lines. Hexane, dichloromethane, ethyl acetate and methanol extracts of Halichondria magniconulosa and Halichondria melanadocia were screened for their cytotoxic activity against hormone-dependent breast cancer (MCF-7) and human cervix cancer (SiHa) cell lines. The ethyl acetate extract of H. magniconulosa exhibited significant cytotoxicity against MCF-7 cells to a CC50 of 0.8 µg/mL, as well as high selectivity (SI = 24.5). On the other hand, SiHa cells were moderately sensitive to the dichloromethane and ethyl acetate extracts of the same species. (CC50 = 34.9 and 31.5 µg/mL, respectively). None of the extracts of H. melanadocia were considered active due their CC50’s were ranged from 59.0 to 94.5 µg/mL.

Apoptosis-inducing activity of safflower (Carthamus tinctorius L.) seed oil in lung, colorectal and cervix cancer cells

Carthamus tinctorius L. (Safflower) has been often preferred because of rich fatty acid, flavonoid, alkaloid, and polysaccharide contents in its different parts in medicine and industrial area. Although its antioxidant, antienflamatuar, and antitumor properties have been proven in many studies, the mechanism underlying the anticancer activity is still more unclear. This study was first conducted to elucidate the apoptotic gene expression changes in human colorectal (CaCo-2), lung (A549), and cervix cancer (HeLa) cells after exposure to safflower seed oil (SFO). Cytotoxic activity of cancer cells was evaluated by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl2H-tetrazoliumbromide) assay and then, total RNA derived from cell lines to analyze the gene expression profile on Real-Time Ready Human Apoptosis Panel 96 was used. MTT results showed that SFO greatly inhibited A549, CaCo-2 and HeLa cell proliferation, with a value of IC50 of 1.26, 3.92 and 13.12 μg/ml, respectively. According to the cDNA microarray analysis, 56 genes were interpreted in connection with extrinsic, intrinsic, PI3K/AKT, JAK/STAT, and NFκB pathways. SFO treatments triggered apoptosis through the caspase-dependently pathway along with upregulated the expressions of many pro-apoptotic genes in the extrinsic and intrinsic pathway in HeLa cells. However, in A549 and CaCo-2 cells, SFO treatments were inhibited cell survival mechanism through frequently caspase-independent genes following downregulated the expression of anti-apoptotic genes. It is noteworthy that although cancer cells have different sensitivity, SFO induced apoptosis through different pathways. Taken together, SFO, as a natural resource, has the potential to be used as a promising agent against cancer, especially in gene therapy level.

An In Vitro Study on the Interactions of Pycnogenol® with Cisplatin in Human Cervical Cancer Cells.

In the treatment of cancer, it is intended to increase the anticancer effect and decrease cytotoxicity using various plant-derived phenolic compounds with chemotherapeutic drugs. Pycnogenol® (PYC), a phenolic compound, has been the subject of many studies. Since the mechanisms of the interactions of PYC with cisplatin need to be clarified, we aimed to determine the effects of PYC on cisplatin cytotoxicity in human cervix cancer cells (HeLa) and to evaluate the genotoxicity of PYC. The cytotoxicity of cisplatin and PYC was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in HeLa cells for 24 h and 48 h. The effect of PYC against oxidative DNA damage was evaluated using the comet assay. The IC50 values of cisplatin were 22.4 μM and 12.3 μM for 24 h and 48 h, respectively. The IC50 values of PYC were 261 μM and 213 μM for 24 h and 48 h, respectively. For 24 h exposure, PYC significantly reduced the IC50 value of cisplatin at the selected concentrations (15.6-500 μM). For 48 h exposure, PYC did not change the cytotoxicity of cisplatin at concentrations between 15.6 and 125 μM, but significantly reduced it at concentrations of 250 μM and 500 μM. PYC alone did not induce DNA damage at concentrations of 10 μM or 25 μM; however, it significantly induced DNA damage at higher concentrations (50-100 μM). It also significantly reduced H2O2-induced DNA damage at all concentrations studied (10-100 μM). Our results suggest that PYC may increase the cisplatin cytotoxicity in HeLa cells at nongenotoxic doses. The results might contribute to the anticancer effect of cisplatin with PYC in cervical carcinoma, but in order to confirm this result further in vitro studies with cancer cell lines and in vivo studies are needed.

Better Therapeutic Target to Enhance Cisplatin Sensitivity in Cervical Cancer: PARP-1 or β-catenin

Development of resistance to cisplatin (CDDP) is a major bottleneck to treat cancer with CDDP, including cervical cancer (CC). We have recently shown that PARP-1 inhibition targets β-catenin signaling and enhance CDDP sensitivity in cervical cancer. This indicates that β-catenin itself could serve as an absolute target to potentiate CDDP cytotoxicity. So, we determined the effect of β-catenin inhibition using JW74 either alone or in combination CDDP using CC cell lines on cell vaibility, apoptosis, cell cycle progression, proliferation, invasion and metastasis, clonogenecity. However, unexpectedly β-catenin inhibitor JW74 failed to significantly enhance CDDP- cytotoxicity in both the cell lines. Since PARP-1 inhibitors inhibited β-catenin also, as determined through our previous work, so, we evaluated effect of JW74 mediated β-catenin inhibition on PARP-1 expression level inside cell. Intriguingly, we found that JW74 treatment enhanced PARP-1 expression as determined through western blotting. Increased PARP-1 serves responsible for CDDP resistance, thereby this seems stands responsible limiting our hypothesis. Further to confirm this, PARP-1 inhibitor PJ34 was added to a combination of JW74+CDDP and this significantly reduced cell survival and proliferation, enhanced cell death and decreased invasion and migration, hence enhanced CDDP sensitivity in CC cells. PJ34 with CDDP served as a better combination to increase caspase-3/7 cleavage, hence apoptosis, than combination of JW74 and CDDP; with PJ34 itself being less toxic to cells. Also PARP-1 expression was determined in human cervical cancer tissue sample at base level and compared to normal tissue sample. PARP-1 expression was significantly enhanced in human cervix cancer tumor samples. In summary, β-catenin inhibition increases PARP-1 expression, thereby, limits ability of β -catenin inhibitors to enhance CDDP cytotoxicity. Enhanced PARP-1 expression in cervix cancer tissue samples shows feasibility of using PARP-1 inhibitors in cervical cancer treatment.