Current Molecular Medicine

Studying Adsorption and Cellular Toxicity of Boron Nitride Nanostructure versus Melphalan Anti-ovarian Cancer Drug

Background: Inclusion of anticancer drugs into biocompatible nanoparticulate carriers decreases the general toxicity and improves the efficacy of clinical treatments due to the reduction of soluble circulating free drugs. Methods: In addition, removal of emerging drug contaminants from wastewaters is a necessity that should be seriously attended. Boron nitride (BN) is a choice in drug delivery because of its many surprising properties. Here, boron nitride nanoparticles are prepared, characterized by Fourier-transform infrared spectroscopy (FT-IR) and x-ray diffraction (XRD) and used in the delivery of melphalan anti-cancer drug. Results: Then, density functional theory (DFT) calculations are carried out to study the adsorption of this drug on the surface of pure boron nitride fullerene via familiar hybrid functionals B3LYP and B3PW91. In addition, the polarizable continuum model (PCM) calculations show that BN is stable in water. Conclusion: Finally, the in vitro cellular toxicity and viability of BN nanoparticles was examined on ES-2 cancer cells. The inhibitory dose IC50 of the material confirmed acceptable cytotoxicity and nanoparticles affected the average growth of the ES-2 cancer cells.

A Comprehensive Review on Cross-talk of Human Papilloma Virus Oncoproteins and Developmental/Self-Renewal Pathways During the Pathogenesis of Uterine Cervical Cancer

Cervical cancer, cancer arising from the uterine cervix, has been regarded as the fourth most frequent gynecological malignancy among females worldwide. Epidemiological reports have shown that uterine cervical cancer is a global health issue among women of especially developing countries and consequently creates an economic and medical burden in the society. The main causative agent of cervical carcinoma is high-risk human papilloma virus (HPV 16 and HPV 18). Molecular studies have revealed the expression of two viral genes E6 and E7, after HPV infection in the epithelial cells of the cervix. These gene products are known to inactivate the major tumor suppressors, p53 and retinoblastoma protein (pRB), respectively. Moreover, the role of self-renewal pathways, such as Hedgehog, Notch, and Wnt, has also been linked with drug resistance in cancer cells and epithelial mesenchymal transition during metastasis in the pathogenesis of cervical cancer. Although the mechanism of interaction of HPV E6 and E7 with each and every component of the above described developmental pathways is not elucidated yet, preliminary reports of their cross-talk have begun to emerge. Understanding the interplay between these oncoproteins and developmental/self-renewal pathways is highly important in terms of designing new and targeted therapeutic approaches against cervical cancer. Hence, this review cynosure the carcinogenesis of HPV with a brief description of its virology and also establishes the cross-talk between oncoproteins E6 and E7 and Hedgehog, Notch, and Wnt signaling pathway.

The Diverse Roles of Long Non-Coding RNA HOTTIP in Breast and Gynecological Cancer Progression

Long non-coding RNAs (lncRNAs) play vital roles in the development and progression of various tumors through multiple mechanisms. Among these, HOTTIP (HOXA transcript at the distal tip) stands out as an intriguing candidate with diverse functions in several malignancies, including breast cancer and gynecologic cancers such as ovarian, cervical, and endometrial cancers, which are significant global health concerns. HOTTIP interacts with key signaling pathways associated with these cancers, including Wnt/β-catenin, PI3K/AKT, and MEK/ERK pathways, enhancing their activation and downstream effects. Its influence extends to crucial aspects of cancer biology, such as cell proliferation, apoptosis, migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT). Additionally, HOTTIP plays a pivotal role in the pathogenesis of breast and gynecologic tumors by sponging various microRNAs (miRNAs) and regulating the expression of mRNAs involved in critical molecular processes. This dysregulation is often associated with poor clinical outcomes, advanced disease stages, and distant metastases. Understanding the functional roles of HOTTIP in these cancers is essential for developing targeted therapeutic strategies. This review aims to explore the emerging roles of HOTTIP in breast and gynecologic cancers.

Morphine-Induced Elevation of Reactive Oxygen Species Attenuates Chemotherapy Efficacy in Diverse Cancer Cell Types

Background: Morphine, a mu-opioid receptor (MOR) agonist commonly utilized in clinical settings alongside chemotherapy to manage chronic pain in cancer patients, has exhibited contradictory effects on cancer, displaying specificity toward certain cancer types and doses. Objective: The aim of this study was to conduct a systematic assessment and comparison of the impacts of morphine on three distinct cancer models in a preclinical setting. Methods: Viability and apoptosis assays were conducted on a panel of cancer cell lines following treatment with morphine, chemotherapy drugs alone, or their combination. Oxidative stress levels, along with the activities of superoxide dismutase and catalase, were measured. Rescue studies were also carried out using antioxidant reagents. Results: Morphine induces resistance to conventional chemotherapeutic agents. It was observed that while morphine affected cell viability differently among ovarian cancer, anaplastic thyroid cancer, and oral squamous cell carcinoma, at concentrations that did not directly impact cancer cell viability, it significantly mitigated the inhibitory effects of chemotherapeutic agents across all tested cancer cells. This phenomenon persisted irrespective of the chemotherapeutic agent used, including cisplatin, doxorubicin, and 5-FU. It remained unaffected by adding naloxone, the MOR receptor antagonist, indicating that morphine's mechanism is independent of the μ- opioid receptor. Moreover, it was demonstrated that morphine heightened cellular reactive oxygen species (ROS) levels and suppressed the activities of superoxide dismutase and catalase. Rescue studies revealed that the addition of antioxidant reversed the protective impact of morphine on cancer cells against chemotherapy. Conclusion: These findings hold promise in potentially guiding the clinical application of morphine for cancer patients undergoing chemotherapy.

miR-34 as a Critical Regulator in Ovarian Cancer

Ovarian cancer (OC) is a gynecologic disease characterized by the uncontrolled growth and proliferation of abnormal cells in the ovaries, fallopian tubes, or peritoneum. Emerging evidence has shown the pivotal role of non-coding RNAs (ncRNAs), such as miRNAs, in driving the pathogenesis of OC. miRNAs are recognized as small ncRNAs that play critical roles in regulating gene expression in normal development and in disease states, including OC. Among miRNAs, the expression of miR-34a was found to be downregulated in OC. Elevated levels of this miRNA are associated with the induction of apoptosis and the inhibition of OC cell proliferation by targeting various signaling pathways, including NOTCH1, P21/P53, STAT3, and BCL2 in OC. Therefore, miR-34a can be a therapeutic target in the management of OC. In this review, we summarized the functional significance of this miRNA in the treatment of OC.

KDM4A Silencing Reverses Cisplatin Resistance in Ovarian Cancer Cells by Reducing Mitophagy via SNCA Transcriptional Inactivation

Background: Ovarian cancer is one of the deadliest gynecologic cancers, with chemotherapy resistance as the greatest clinical challenge. Autophagy occurrence is associated with cisplatin (DDP)-resistant ovarian cancer cells. Herein, the role and mechanism of alpha-synuclein (SNCA), the autophagy-related gene, in DDP resistance of ovarian cancer cells are explored. Methods: Differentially expressed genes in DDP resistance of ovarian cancer cells were analyzed by GEO2R tools. DDP-resistant ovarian cancer cells (A2780/DDP) were transfected and treated with 2.5 μg/mL DDP for 72 h, followed by the determination of cell viability, proliferation, apoptosis, and expressions of SNCA, lysine demethylase 4A (KDM4A), histone H3 lysine 9 trimethylation (H3K9me3), and mitophagy-related proteins. The H3K9me3 demethylation of SNCA by KDM4A was confirmed by chromatin immunoprecipitation. Results: SNCA and KDM4A were highly expressed in DDP-resistant ovarian cancer cells and their parental cells. KDM4A knockdown diminished expressions of KDM4A and SNCA and elevated H3K9me3 expression and H3K9me3 enrichment on SNCA promoter in A2780/DDP cells. SNCA or KDM4A knockdown inhibited cell viability, proliferation, and levels of LC3-II/LC3-I and Parkin while inducing cell apoptosis and upregulating Cyt-C expression of A2780/DDP cells with/without DDP treatment; however, SNCA overexpression not only did conversely but also reversed the effects of KDM4A knockdown on DDP-treated A2780/DDP cells and vice versa. Conclusion: Silencing of KDM4A-mediated transcription inactivation of SNCA reduces mitophagy, thus inhibiting the resistance of ovarian cancer cells to cisplatin. KDM4A may be a promising drug target for DDP-resistant ovarian cancer cells.

The Roles of Autophagy-related miRNAs in Gynecologic Tumors: A Review of Current Knowledge for Possible Targeted Therapy

: Gynecological cancers are the leading cause of malignancy-related death and disability in the world. These cancers are diagnosed at end stages, and unfortunately, the standard therapeutic strategies available for the treatment of affected women [including chemotherapy, radiotherapy and surgery] are not safe and effective enough. Moreover, the unwanted side-effects lowering the patients' life quality is another problem for these therapies. Therefore, researchers should search for better alternative/complementary treatments. The involvement of autophagy in the pathogenesis of various cancers has been demonstrated. Recently, a novel crosstalk between microRNAs, small non-coding RNAs with important regulatory functions, and autophagy machinery has been highlighted. In this review, we indicate the importance of this interaction for targeted therapy in the treatment of cancers including gynecological cancers, with a focus on underlying mechanisms.