Search Results (175)

Artocarpus heterophyllus (jackfruit) is widely distributed in subtropical and tropical regions, and some phytochemicals isolated from this species have demonstrated anti-proliferative effects. However, its impact on triple-negative breast cancer (TNBC) and HPV-related cervical cancer models remains unclear. This study evaluated the phytochemical profile and anticancer activity of an ethanolic extract from A. heterophyllus leaves (AHEE) in the TNBC cell line MDA-MB-231 and in the HPV-16⁺ murine cancer cell line TC-1. Phytochemical screening and spectroscopic analyses (UV-Vis, IR, ¹H, and ¹³C NMR) revealed the presence of tannins, alkaloids, steroids, coumarins, and flavone-type flavonoids, with a total phenolic content of 3.34 µg GAE/mg and flavonoid content of 0.44 mg QE/g extract. In 2D cultures, AHEE reduced cell viability by 49% in TC-1 and 24% in MDA-MB-231 at 300 µg/mL, inhibited colony formation and migration in TC-1, and impaired survival but not migration in MDA-MB-231. In 3D cultures, 250 µg/mL inhibited proliferation, migration, and anchorage-independent growth in both cell lines. Furthermore, the combination of AHEE with one-fifth of the IC₅₀ of doxorubicin or cisplatin produces an effect comparable to that observed with the full IC₅₀ of these drugs. These findings suggest that AHEE possesses anticancer activity with cell-type-specific effects and highlight its potential as an adjuvant therapy. Further studies are warranted to elucidate its mechanisms of action. Full article

The present study examined the impact of germination using Aloe vera as an elicitor on the phytochemical composition, antioxidant capacity, and in vitro anti-hyperglycemic and antitumoral activity of fenugreek seed extracts germinated by pressurized n-propane. The lipid composition, free fatty acids, antioxidant activity, and phenolic content, as well as the contents of α-tocopherol, β-carotene, and minor compounds, have been determined for the extracts. The in vitro anti-hyperglycemic and anticancer activities were also evaluated in cervical cancer (HeLa) and colon cancer (SiHa) cell lines. Antioxidant activity increased two-fold, α-tocopherol increased almost three-fold, and β-carotene content was 55% higher in the germinated seed extracts compared to the raw. Fifteen polyphenolic compounds have been identified in fenugreek seed extracts, which promote germination by increasing high levels of polyunsaturated fatty acids at the expense of reducing saturated fatty acids. Extracts obtained from seed germination and elicitation with Aloe vera demonstrated potential in vitro anticancer activity in HeLa and SiHa cells. Fenugreek extracts demonstrated high in vitro inhibition of α-glucosidase (99%) and α-amylase (95%), indicating anti-hyperglycemic potential. The use of Aloe vera germination, combined with extraction using pressurized n-propane, demonstrated efficiency in enriching fenugreek seed extracts with bioactive compounds with potential in vitro anti-hyperglycemic and antitumor activity. Full article

Gallic acid is a natural phenolic acid that displays potent anti-cancer activity in a large variety of cell types and rodent cancer xenograft models. Although research has focused on determining the efficacy of gallic acid against various types of human cancer cells, the molecular mechanisms governing the anti-cancer properties of gallic acid remain largely unclear, and a transcriptomic study of gallic acid-induced cancer cell death has rarely been reported. Therefore, we applied time-course bulk RNA-sequencing to elucidate the molecular signature of gallic acid-induced cell death in human cervical cancer HeLa cells, as this is a widely used in vitro model in the field. Our RNA-sequencing dataset covers the early (2^nd hour), middle (4^th, 6^th hour), and late (9^th hour) stages of the cell death process after exposure of HeLa cells to gallic acid, and the untreated (0^th hour) cells served as controls. Differential expression of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) was identified at each time point in the dataset. In summary, this dataset is a unique and valuable resource with which the scientific community can explore the molecular mechanisms and identify druggable regulators of the gallic acid-induced cell death process in cancer. Full article

Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D₃ inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D₃ and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D₃ and 1,25(OH)₂D_3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D₃ holds immense potential as a complementary therapeutic treatment for cervical cancer. Full article

A new alkaloid (orychophragvioline A) and nine known compounds were yielded from the seeds of Orychophragmus violaceus. Their structures were determined by various spectroscopic techniques and single-crystal X-ray diffraction. Orychophragvioline A is a rare alkaloid with an unusual 1-methyl-4-phenyl-2,3-diketopiperazine skeleton connected with a guanidine group via an amide bond. The results of antitumor tests in vitro showed that it exhibited prominent cytotoxicity against Hela cells with an IC₅₀ value of 11.95 ± 1.52 μM. Further investigations suggested that it significantly inhibited cellular proliferation, migration, and invasion in a dose-dependent manner, thus inducing the apoptosis of Hela cells. These findings indicate that orychophragvioline A can be regarded as a potential natural leading compound against cervical cancer. Full article

Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed. The newly developed dual topoisomerase inhibitor P8-D6, with its outstanding ability to induce apoptosis, could be a promising option. In this study, the efficacy of P8-D6 in combination with radiochemotherapy against cervical carcinoma was investigated in established cell lines and in a translational approach in ex vivo patient cells by measuring the cytotoxicity, cell viability and caspase activity in vitro in 2D and 3D cell cultures. Treatment with P8-D6 resulted in significantly greater cytotoxicity and apoptosis induction compared to standard therapeutic cisplatin in both 2D and 3D cell cultures. Specifically, a considerably stronger anti-proliferative effect was observed. The treatment also led to morphological changes and a loss of membrane integrity in the 3D spheroids. Radiotherapy also benefited greatly from P8-D6 treatment. In fact, P8-D6 was a more potent radiosensitizer than cisplatin. Simple synthesis, favorable physicochemical properties and high potency make P8-D6 a promising cervical cancer drug candidate. Full article

Among aquatic organisms, marine dinoflagellates are essential sources of bioactive metabolites. The benthic dinoflagellate Coolia malayensis produces metabolites that have exhibited substantial and specific cytotoxicity on cancer cells; however, isolation and identification of the purified compounds remain a challenge. This study reports C. malayensis biomass multi-step extraction plus chemical analyses for identifying compounds with antineoplastic activity. Through bio-directed fractionation, the cytotoxicity of extracts and fractions was tested on H1299 (lung), PC-3 (prostate), HeLa (cervical), and MCF-7 (breast) cancer cell lines. Dichloromethane (DCM) phase, hydroalcoholic (HYD) secondary extract, and methanolic (MET) extract showed cytotoxic effects on all cell lines. Active extracts and fractions were analyzed by HPLC-QTOF-MS, ¹H, and ¹³C NMR. Cell lines H1299 and PC-3 treated with fractions F4, F7, and DCM2-AQ-Ch sub-extract showed morphological changes resembling those observed in the apoptosis control, and no signs of necrosis were observed. The selectivity of fraction F7 was above 100 μg mL⁻¹ for healthy cells, while cytotoxic activity was observed in cancer cells. This fraction was identified as mostly fatty acids (FA) by NMR. Seventeen compounds with reported biological activities, such as antioxidant, analgesic, antiviral, and anticancer, were identified from C. malayensis extracts and fractions. Among them, the phycotoxins gambieric acid A and B, okadaic acid, and dinophysistoxin-1 were detected. Further studies are needed to reveal more significant anti-cancer potential from C. malayensis. Full article

Pueraria lobata (Willd.) has been used as food since ancient times, and its roots have been used mainly as a traditional herbal medicine to treat various diseases in East Asia. Puerarin is one of the major active ingredients in the roots of P. lobata. The purpose of this study was to examine the effects of the methanol extract of P. lobata roots (PRME) and puerarin on apoptosis in cervical cancer and inflammation-relieving effects in vaginitis. First, we prepared the PRME and confirmed the puerarin content of PRME through HPLC analysis. We performed a TUNEL assay, Hoechst 33342 staining, and western blotting using HeLa cells, a human cervical cancer cell line. Both the PRME and puerarin exhibited antiproliferative effects in HeLa cells by inducing apoptosis through the activation of the extrinsic death receptor and intrinsic mitochondrial pathways, thereby demonstrating their anticancer efficacy against human cervical cancer. Next, a mouse model of vaginitis induced by Gardnerella vaginalis (GV) infection was established by inoculating C57BL/6 mice with β-estradiol-3-benzoate and GV (1 × 10⁸ CFU). Histological analysis and PCR confirmed that the administration of PRME or puerarin to GV-infected mice alleviated reproductive tract vaginitis symptoms. Additionally, we confirmed that PRME or puerarin treatment decreased myeloperoxidase activity and reduced inflammation by regulating cytokines through the secretion of inflammatory mediators in mouse vaginal tissue. These results demonstrate that PRME and puerarin can be used as potential adjuvants or therapeutic agents with anticancer and anti-inflammatory properties to inhibit the progression of human cervical cancer and alleviate vaginitis. Full article

Background: The clinical efficacies of anticancer drugs are limited by non-selective toxic effects on healthy tissues and low bioavailability in tumor tissue. Therefore, the development of vehicles that can selectively deliver and release drugs at the tumor site is critical for further improvements in patient survival. Methods: We prepared a CEC nano-drug delivery system, CEC@ZIF-8, with a zeolite imidazole framework-8 (ZIF-8) as a carrier, which can achieve the response of folate receptor (FR). We characterized this system in terms of morphology, particle size, zeta potential, infrared (IR), x-ray diffraction (XRD), and transcriptome analysis, and examined the in vitro cytotoxicity and cellular uptake properties of CEC@ZIF-8 using cervical cancer cells. Lastly, we established a TC-1 tumor-bearing mouse model and evaluated its in vivo anti-cervical cancer activity. Results: The CEC@ZIF-8 nano-delivery system had favorable biocompatibility, heat stability, and pH responsiveness, with a CEC loading efficiency of 12%, a hydrated particle size of 174 ± 5.8 nm, a zeta potential of 20.57 mV, and slow and massive drug release in an acidic environment (pH 5.5), whereas release was 6% in a neutral environment (pH 7.4). At the same time, confocal imaging and cell viability assays demonstrated greater intracellular accumulation and more potent cytotoxicity against cancer cells compared to free CEC. The mechanism was analyzed by a series of transcriptome analyses, which revealed that CEC@ZIF-8 NPs differentially regulate the expression levels of 1057 genes in cancer cells, and indicated that the enriched pathways were mainly cell cycle and apoptosis-related pathways via the enrichment analysis of the differential genes. Flow cytometry showed that CEC@ZIF-8 NPs inhibited the growth of HeLa cells by arresting the cell cycle at the G0/G1 phase. Flow cytometry also revealed that CEC@ZIF-8 NPs induced greater apoptosis rates than CEC, while unloaded ZIF-8 had little inherent pro-apoptotic activity. Furthermore, the levels of reactive oxygen species (ROS) were also upregulated by CEC@ZIF-8 NPs while ROS inhibitors and caspase inhibitors reversed CEC@ZIF-8 NPs-induced apoptosis. Finally, CEC@ZIF-8 NPs also reduced the growth rate of xenograft tumors in mice without the systemic toxicity observed with cisplatin treatment. Conclusions: The CEC@ZIF-8 nano-drug delivery system significantly enhanced the anti-cervical cancer effect of CEC both in vivo and in vitro, providing a more promising drug delivery system for clinical applications and tumor management. At the same time, this work demonstrates the clinical potential of CEC-loaded ZIF-8 nanoparticles for the selective destruction of tumor tissues. Full article

Background: Cervical cancer is a type of cancer that originates from the endometrium and is more common in developed countries and its incidence is increasing day by day in developing countries. The most commonly prescribed chemotherapeutic drugs limit their use due to serious side effects and the development of drug resistance. For this reason, interest in new active ingredients obtained from natural products is increasing. This study aimed to reveal the apoptotic and antiproliferative effects of gallic acid and doxorubicin combination therapy against the HeLa cell line. Methods: We investigated the anti-cancer effects of doxorubicin and gallic acid in the human HeLa cervical cell line by using the MTT test, Nucblue staining for the identification of apoptotic cells due to nuclear condensation using fluorescent substance, and apoptotic markers P53 and Bax for the RT-PCR test. Results: The highest cytotoxic effect obtained in the study, the highest increase in apoptotic induction, and a significant difference in P53/Bax levels were seen in the gallic acid/doxorubicin combination. Additionally, it was determined that gallic acid exhibited an effective cytotoxic effect on HeLa and HaCat cells within 48 and 72 h of application. Conclusions: The obtained findings show that the gallic acid/doxorubicin combination applied to HeLa cells may be an alternative treatment against both the cytotoxic effect size and the side effects of the chemotherapy agent. Full article

Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers. Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group. Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models. Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment. Full article

Background/Objectives: Luteolin (LUT) is a natural flavonoid with known anti-inflammatory, antioxidant, and anti-cancer properties. Cervical cancer, particularly prevalent in certain regions, remains a significant health challenge due to its high recurrence and poor response to treatment. This study aimed to investigate the anti-tumor effects of LUT on human cervical epidermoid carcinoma cells (Ca Ski), focusing on cell growth inhibition, apoptosis induction, and regulation of mitochondrial membrane potential. Methods: Ca Ski cells were treated with varying concentrations of LUT (0, 25, 50, 100 µM) for different time periods (24, 48, 72 hours). Cell viability was measured using the MTT assay, apoptosis was assessed by flow cytometry with annexin V-FITC/PI staining, and changes in mitochondrial membrane potential were evaluated using JC-1 staining. Caspase-3 activation was examined by flow cytometry, and expression of apoptosis-related proteins (caspase-3, -8, -9, AIF) was analyzed via Western blotting. Results: LUT significantly inhibited the growth of Ca Ski cells in a dose- and time-dependent manner, with the most pronounced effects observed at 100 µM over 72 hours. Flow cytometry confirmed that LUT induced apoptosis without causing necrosis. Mitochondrial membrane potential was reduced after LUT treatment, coinciding with increased caspase-3 activation. Western blot analysis revealed the upregulation of pro-apoptotic proteins caspase-3, -8, -9, and AIF, indicating that LUT induces apoptosis through the intrinsic mitochondrial pathway. Conclusions: Luteolin effectively inhibits cervical cancer cell proliferation and induces apoptosis by disrupting mitochondrial membrane potential and activating caspases. These findings suggest that LUT holds potential as a therapeutic agent for cervical cancer, with further studies needed to explore its in vivo efficacy and broader clinical applications. Full article

Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia. Full article

Four new alkaloids, vibripyrrolidine A (1), vibripiperazine A (2), and vibridiazinane A, B (3, 4), comprising one pyrrolidine, one piperazine, and two diazinane alkaloids, along with two known analogs (5, 6), were isolated from the marine bacterium Vibrio ruber ZXR-93 cultured in ISP2 medium. Their chemical structures were elucidated by analysis of their 1D and 2D NMR, mass spectra, and electronic circular dichroism (ECD) calculations. Compounds 1 and 3–6 showed vigorous antibacterial activity against Staphylococcus aureus, with MIC values ranging from 0.96 to 7.81 μg/mL. Moreover, compound 1 exhibited robust anti-inflammatory activity in vitro using the LPS-induced RAW264.7 macrophage model. All compounds also showed moderate antineoplastic activity against cervical cancer cells (HeLa) and gastric cancer cells (SGC-7901). Full article

Previously, we showed the antitumor activity of the new NOS/PDK inhibitor T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). The present study included an assessment of in vitro cytotoxicity against human malignant and normal cells according to the MTT-test and in vivo antitumor effects in solid tumor models in comparison with precursor compounds T1023 (NOS inhibitor; 1-isobutanoyl-2-isopropylisothiourea hydrobromide) and Na-DCA (PDK inhibitor; sodium dichloroacetate), using morphological, histological, and immunohistochemical methods. The effects of T1084 and T1023 on the in vitro survival of normal (MRC-5) and most malignant cells (A375, MFC-7, K562, OAW42, and PC-3) were similar and quantitatively equal. At the same time, melanoma A375 cells showed 2–2.5 times higher sensitivity (IC₅₀: 0.39–0.41 mM) to the cytotoxicity of T1023 and T1084 than other cells. And only HeLa cells showed significantly higher sensitivity to the cytotoxicity of T1084 compared to T1023 (IC₅₀: 0.54 ± 0.03 and 0.81 ± 0.02 mM). Comparative studies of the in vivo antitumor effects of Na-DCA, T1023, and T1084 on CC-5 cervical cancer and B-16 melanoma in mice were conducted with subchronic daily i.p. administration of these agents at an equimolar dose of 0.22 mmol/kg (33.6, 60.0, and 70.7 mg/kg, respectively). Cervical cancer CC-5 fairly quickly evaded the effects of both Na-DCA and T1023. So, from the end of the first week of Na-DCA or T1023 treatment, the tumor growth inhibition (TGI) began to decrease from 40% to an insignificant level by the end of the observation. In contrast, in two independent experiments, CC-5 showed consistently high sensitivity to the action of T1084: a significant antitumor effect with high TGI (43–58%) was registered throughout the observation, without any signs of neoplasia adaptation. The effect of precursor compounds on melanoma B-16 was either minimal (for Na-DCA) or moderate (for T1023) with TGI only 33%, which subsequently decreased by the end of the experiment. In contrast, the effect of T1084 on B-16 was qualitatively more pronounced and steadily increasing; it was accompanied by a 3-fold expansion of necrosis and dystrophy areas, a decrease in proliferation, and increased apoptosis of tumor cells. Morphologically, the T1084 effect was 2-fold superior to the effects of T1023—the TGI index reached 59–62%. This study suggests that the antitumor effects of T1084 develop through the interaction of NOS-dependent and PDK-dependent pathophysiological effects of this NOS/PDK inhibitor. The NOS inhibitory activity of T1084 exerts an anti-angiogenic effect on neoplasia. At the same time, the PDK inhibitory activity of T1084 enhances the cytotoxicity of induced intratumoral hypoxia and suppresses the development of neoplasia adaptation to anti-angiogenic stress. Such properties allow T1084 to overcome tumor resistance and realize a stable synergistic antitumor effect. Full article