Beyond Hormones: Investigating the Impact of Progesterone Receptor Membrane Component 1 in Lung Adenocarcinoma.

Progesterone Receptor Membrane Component 1 (PGRMC1) is a candidate oncogene with a prominent involvement in the pathogenesis of diverse cancers (ovarian, thyroid, breast, colon, head, and neck). Our study ascertains the ability of PGRMC1 to influence WNT members in the non-small cell lung cancer subtype-lung adenocarcinoma (LUAD) and participates in augmented cell proliferation and migration. Both computational and in vitro experimental analyses were performed in this study. Gene silencing, in vitro assays, gene expression & and protein expression studies were performed to ascertain the role of PGRMC1 in LUAD cells. The computational analysis, PGRMC1 gene level expression was analysed using the microarray gene expression omnibus datasets (GSE27262; GSE18842) to compare LUAD tumours and normal tissues. Concurrently, the gene expression profiling interactive analysis of PGRMC1 and Kaplan-Meier survival analysis revealed a decreasing patient survival rate with an increasing PGRMC1 gene expression in LUAD tumour samples. Interestingly, the experimental gene silencing studies were conducted in vitro (si-PGRMC1 Vs si-Control) to understand the essential role of PGRMC1 in regulating WNT-associated genes (WNT1, WNT5A, and WNT11). Comparative experimental cell migration and spheroid formation assays (si-PGRMC1 Vs si-Control) in vitro showed a strong association between PGRMC1 and LUAD. In vitro expression analysis using real-time PCR and western blot further confirmed the connecting link between PGRMC1 and WNT5A compared to other WNT member genes (WNT1 and WNT11) in LUAD. The computational and experimental analyses agreed with one another.

Impact of xenobiotic-metabolizing gene polymorphisms on breast cancer risk in South Indian women.

BACKGROUND: Functional variants of the xenobiotic-metabolizing genes (XMG) might modulate breast cancer (BC) risk by altering the rate of metabolism and clearance of myriad types of potent carcinogens from the breast tissue. Despite mounting evidence on the role of XMG variants on BC risk, the current knowledge regarding their influence on BC development is still fragmentary. METHODS: The present study examined the candidate genetic variants in CYP1A1, NQO1, GST-T1, GST-M1, and GST-P1 in 1002 subjects (502 BC patients and 500 disease-free women). PCR-RFLP was employed to genotype the mono-nucleotide variation in CYP1A1, NQO1, and GST-P1, and allele-specific PCR was used to detect the deletion polymorphism in GST-T1 and GST-M1 genes. RESULTS: Regarding CYP1A1-M1 polymorphism, the heterozygous TC and mutant CC genotype conferred 1.47-fold (95% CI 1.13-1.91, p = 0.004) and 1.84-fold (95% CI 1.17-2.91, p = 0.009) elevated risk of BC. GST-T1 null genotype was associated with increased BC risk (OR 1.47; 95% CI 1.02-2.11, p = 0.037). For the NQO1 C609T variant, the mutant T allele was associated with BC risk with an odds ratio of 1.22 (95% CI 1.02-1.48, p = 0.034). Combinatorial analysis indicated that the presence of NQO1*2 (CT), CYP1A1-M1 (CC), and GST-P1 rs1695 (AG) genotypes conferred 16.7-fold elevated risk of BC (95% CI 3.65-76.85; p < 0.001). Moreover, GST-M1 null genotype was associated with the development of larger primary breast tumors. CONCLUSION: Xenobiotic-metabolizing gene polymorphisms may play a crucial role in mammary carcinogenesis in South Indian women.

The impact of fusion genes on cancer stem cells and drug resistance.

With ever increasing evidences on the role of fusion genes as the oncogenic protagonists in myriad cancers, it's time to explore if fusion genes can be the next generational drug targets in meeting the current demands of higher drug efficacy. Eliminating cancer stem cells (CSC) has become the current focus; however, we have reached a standstill in drug development owing to the lack of effective strategies to eradicate CSC. We believe that fusion genes could be the novel targets to overcome this limitation. The intriguing feature of fusion genes is that it dominantly impacts every aspect of CSC including self-renewal, differentiation, lineage commitment, tumorigenicity and stemness. Given the clinical success of fusion gene-based drugs in hematological cancers, our attempt to target fusion genes in eradicating CSC can be rewarding. As fusion genes are expressed explicitly in cancer cells, eradicating CSC by targeting fusion genes provides yet an another advantage of negligible patient side effects since normal cells remain unaffected by the drug. We hereby delineate the latest evidences on how fusion genes regulate CSC and drug resistance.

Overview of Morin and Its Complementary Role as an Adjuvant for Anticancer Agents.

The Global cancer incidence and mortality data released by the World Health Organization proposes that out of 18.1 million new cancer cases diagnosed, 9.8 million deaths occurred globally in 2018. Cancer is one of the major health burdens among non-communicable diseases globally responsible for impeding life expectancy in the present century. Disrupting hallmarks of cancer (such as prolonged inflammation, increased growth signal, tissue invasion and metastasis, unlimited proliferation and evasion of apoptosis) with dietary agents is of considerable focus for cancer prevention and therapy. In the last decade, a significant contribution has been provided in finding many plant-derived natural agents that can be identified as promising molecular cancer therapeutics. Our focus in this review is on one such natural dietary agent, Morin (3,5,7,2',4'-pentahydroxyflavone): a bioflavonoid. Morin exerts strong pharmacological properties against a multitude of cancer (liver cancer, cervical cancer, melanoma, breast cancer, prostate, and colon cancer). Recent progress has also been made in examining the potential of morin as a natural dietary agent for fostering the pharmacological effects of other well-known anticancer agents. This review provides an overview of morin and its derivatives in combination with anticancer agents for cancer prevention and therapy.

Multifaceted roles of long non-coding RNAs in triple-negative breast cancer: biology and clinical applications.

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype that lacks targeted therapy due to the absence of estrogen, progesterone, and HER2 receptors. Moreover, TNBC was shown to have a poor prognosis, since it involves aggressive phenotypes that confer significant hindrance to therapeutic treatments. Recent state-of-the-art sequencing technologies have shed light on several long non-coding RNAs (lncRNAs), previously thought to have no biological function and were considered as genomic junk. LncRNAs are involved in various physiological as well as pathological conditions, and play a key role in drug resistance, gene expression, and epigenetic regulation. This review mainly focuses on exploring the multifunctional roles of candidate lncRNAs, and their strong association with TNBC development. We also summarise various emerging research findings that establish novel paradigms of lncRNAs function as oncogenes and/or tumor suppressors in TNBC development, suggesting their role as prospective therapeutic targets.

Geraniin: A dietary ellagitannin as a modulator of signalling pathways in cancer progression.

Cancer remains a global health challenge, necessitating the exploration of novel therapeutic agents. Current treatment options are unable to overwhelm and cure the cancer burden. Hence, identifying new bioactive molecular entities with potent anticancer activity is the need of the hour. Ellagitannin Geraniin (GN) is one such evidence-based novel bioactive molecular entity (BME) available from different natural sources that can effectively combat cancer. This narrative review attempts to investigate the potential of BME-GN from 2005 to 2023 as an efficient molecular anti-cancer therapeutic against diverse cancers. We provide information on GN's pharmacological advantages, metabolite profile, and capacity to modulate multiple molecular targets involved in the hallmarks of cancer. Using the search terms "Geraniin," "Gallic acid," "Ellagitannin," "pharmacological properties," "health," "antioxidant," "apoptosis," "disease management," "anti-proliferative," "in vitro," "anti-inflammatory," "anti-angiogenic," "in vivo," and "clinical trials," We searched the scientific literature using Scopus, Web of Science, Google Scholar, and PubMed. We removed publications that included overlap or equivalent content and used the most recent review on each issue as our primary reference. From an initial pool of 430 articles, 52 studies met the search criteria. These studies collectively provide substantial in vitro, in vivo, and clinical evidence of GN's potential to combat diverse cancers. Mechanistic insights revealed its involvement in fostering apoptosis, anti-inflammatory, and modulation of key signalling pathways implicated in the hallmarks of cancer. GN's pleiotropic pharmacological and molecular therapeutic properties strongly suggest its potential as a promising anticancer agent.

Methyl gallic acid entrapped ethosomal nano-vesicular system augments cytotoxicity against squamous cell carcinoma.

Methylated gallic acid (MGA) is a potent anticancer biomolecular entity (BME). Loading MGA into a nano-vesicular (NV) drug delivery system using nanotechnology approaches can increase the efficiency of the drug and its release characteristics. This study aimed to develop an ethosomal nano-vesicular (ENV) system loaded with MGA that shows augmented entrapment efficiency, release rate, and cytotoxic potential against oral cancer. The ENV system was synthesized using Soy lecithin, ethanol, and propylene glycol. The ENV system's characterization (DLS, Zeta potential, TEM, FT-IR) with and without MGA was performed. The cytotoxicity evaluation of MGA alone compared to the MGA-loaded ENV system was performed against the squamous cell carcinoma-9 (SCC-9) cell line. The DLS and zeta potential analysis revealed the size of the ENV system as 58.2 nm and-43.5 mV charge, respectively. MGA loading to ENV system increased size to 63 nm and decreased charge to -2.8 mV. Peaks of FTIR analysis confirmed the encapsulation of MGA in the ENV system. TEM studies revealed the spherical surface morphology of the MGA-loaded ENV system. Compared with conventional MGA alone administration, ENV loaded with MGA showed better drug absorption and bioavailability in vitro. Furthermore, the entrapment efficiency, in vitro drug release, and cytotoxicity results firmly establish the improved therapeutic potential of ENV loaded with MGA against oral cancer cells than MGA alone. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03652-6.

Ameliorative effect of methanol extract of Rubia cordifolia in N-nitrosodiethylamine-induced hepatocellular carcinoma.

CONTEXT: Rubia cordifolia Linn. (Rubiaceae) is a medicinal plant used in the ayurvedic system of medicine. It is also known as Indian Madder or Manjistha and is traditionally used as an antiinflammatory, antiseptic, and galactopurifier, but its anticancer propertis are yet not known. OBJECTIVE: The ameliorative effect of the Rubia cordifolia methanol extract on N-nitrosodiethylamine-induced experimental hepatocellular carcinogenesis in rats. MATERIALS AND METHODS: Changes in liver weight, serum markers of liver damage, hydroxyl radicals, lipid peroxidation, levels of enzymic and nonenzymic antioxidants; mitochondrial and respiratory chain enzymes were also investigated using various biochemical parameters and histopathological studies. Male albino rats of Wistar strain were divided into four groups for a study period of 3 months. Animals of group I and group IV served as control and drug control, respectively. Hepatocellular carcinoma was induced in animals of groups II and III with 0.02% N-nitrosodiethylamine. RESULTS: Upon Rubia cordifolia methanol extract co-treatment (250, 500, and 750 mg/kg bodyweight) in group III alone levels of serum marker enzymes and antioxidants increased significantly in a dose-dependent manner. The levels of hydroxyl radicals and lipid peroxidation decreased. Mitochondrial enzymes and respiratory chain enzymes, which were decreased in N-nitrosodiethylamine-induced rats, increased significantly in RC treated rats. Further histological analysis of liver confirmed the prevention of pathological changes caused by N-nitrosodiethylamine on Rubia cordifolia supplementation. DISCUSSION AND CONCLUSION: These findings demonstrate that Rubia cordifolia can be a source of potent antioxidants for treatment of diseases such as cancer.

A comprehensive overview on the anti-inflammatory, antitumor, and ferroptosis functions of bromelain: an emerging cysteine protease.

INTRODUCTION: Bromelain belongs to the cysteine protease endopeptidase class of enzymes isolated from the stem and fruit tissue component of Ananas comosus. The commercial and translational therapeutic potential of bromelain is ever increasing due to its augmented stability, easier purification, and salubrious pan-cancer effects. AREAS COVERED: This paper presents the current state of knowledge about the isolation methods of bromelain, its safety, efficacy and tolerability. In addition, bromelains' role in eliciting pharmacological effects and its healing ability to mitigate cancer side effects based on accumulated in vitro, in vivo, and clinical evidence is relatively considerable. EXPERT OPINION: Identification of molecular targets and crucial signalling pathways that bromelain regulates suggest it genuinely prospects for combating cancer and mitigation of chemotherapy or radiotherapy mediated side effects. Further research on the development of bromelain-entrapped drug delivery systems for augmented enzyme stability, processing ability and translational potential against cancer can be beneficial.

Progesterone Receptor Membrane Component 1 and its Accomplice: Emerging Therapeutic Targets in Lung Cancer.

Progesterone receptor membrane component 1 (PGRMC1) is a trans-membrane evolutionarily conserved protein with a cytochrome b5 like heme/steroid binding domain. PGRMC1 clinical levels are strongly suggested to correlate with poor patient survival and lung cancer prognosis. PGRMC1 has been reported to possess pleiotropic functions, such as participating in cellular and membrane trafficking, steroid hormone signaling, cholesterol metabolism and steroidogenesis, glycolysis and mitochondrial energy metabolism, heme transport and homeostasis, neuronal movement and synaptic function, autophagy, anti-apoptosis, stem cell survival and the list is still expanding. PGRMC1 mediates its pleiotropic functions through its ability to interact with multiple binding partners, such as epidermal growth factor receptor (EGFR), sterol regulatory element binding protein cleavage activating protein (SCAP), insulin induced gene-1 protein (Insig-1), heme binding proteins (hepcidin, ferrochelatase and cyp450 members), plasminogen activator inhibitor 1 RNA binding protein (PAIR-BP1). In this review, we provide a comprehensive overview of PGRMC1 and its associated pleiotropic functions that are indispensable for lung cancer promotion and progression, suggesting it as a prospective therapeutic target for intervention. Notably, we have compiled and reported various preclinical studies wherein prospective agonists and antagonists had been tested against PGRMC1 expressing cancer cell lines, suggesting it as a prospective therapeutic target for cancer intervention.

Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective.

Triple-negative breast cancer (TNBC) is one of the most fatal and aggressive type of cancer in younger population. TNBC is poorly diagnosed, detected only at later stages with low survival rate and high chemoresistance. The expression of the cancer stem cell (CSC) markers has critical role in chemoresistance and recurrence. In this review, focus is on potential CSC targets and treatment strategies for TNBC. Inhibition of proliferative genes involved in TNBC can reduce its spread and tumor invasiveness. Also, inhibiting proteins that are involved in signaling pathways that help in the expression of CSC markers can improve chemosensitivity. Thus, combining inhibition of critical genes and proteins can be a potential therapy strategy. Therefore, functioning of γ-secretase inhibitors (GSI-IX, Presenilin1/2, Pen-2, Nicastrin, APH-1), BEZ235, GANT61 inhibitor, NVP-LDE225, GSK3ß inhibitor, AMPK activator (Aza- podophyllotoxin, demethoxycurcumin, N, N-diarylurea FND-4b) and MYC inhibitors (Triptolide, Quinoxalines) in TNBC are reviewed extensively.

Homologous recombination DNA repair gene RAD51, XRCC2 & XRCC3 polymorphisms and breast cancer risk in South Indian women.

BACKGROUND: Homologous recombination repair (HRR) accurately repairs the DNA double-strand breaks (DSBs) and is crucial for genome stability. Genetic polymorphisms in crucial HRR pathway genes might affect genome stability and promote tumorigenesis. Up to our knowledge, the present study is the first to investigate the impact of HRR gene polymorphisms on BC development in South Indian women. The present population-based case-control study investigated the association of polymorphisms in three key HRR genes (XRCC2-Arg188His, XRCC3-Thr241Met and RAD51-G135C) with BC risk. MATERIALS AND METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping the HRR variants in 491 BC cases and 493 healthy women. RESULTS: We observed that the XRCC3 Met allele was significantly associated with BC risk [OR:1.27 (95% CI: 1.02-1.60); p = 0.035]. In addition, the homozygous mutant (C/C) genotype of RAD51 G135C variant conferred 2.19 fold elevated risk of BC [OR: 2.19 (95% CI: 1.06-4.54); p = 0.034]. Stratified analysis of HRR variants and BC clinicopathological features revealed that the XRCC3-Thr241Met and RAD51-G135C variants are associated with BC progression. Combined SNP analysis revealed that the individuals with RAD51-C/C, XRCC2-Arg/Arg, and XRCC3-Thr/Thr genotype combination have three-fold increased BC risk. CONCLUSION: The present study imparts additional evidence that genetic variants in crucial HRR pathway genes might play a pivotal role in modulating BC risk in South Indian women.

Plausible computational insights and new atomic-level perspective of epicathechin gallate from Crataegus oxycantha extract in preventing caspase 3 activation in conditions like post-myocardial infarction.

Cardiovascular disease (CVD) is the leading cause of mortality among the human species, however the non-existence of successful therapies to curtail the effect of Myocardial Infarction (MI) is a disquieting reality. Even though successful herbal formulations using Crataegus oxycantha (COC) is available, however, it is not recognized as an alternative medicine due to the lack of explanation on the molecular mechanism of COC extract on CVD conditions. In vivo studies revealed that COC extract significantly prevented caspase activation in conditions like post-MI; however, the role of a specific secondary metabolite that could be involved in this action is under quest. The present study, therefore, aims at predicting the plausible mechanism of action of key secondary metabolite in COC extract on apoptotic executioner caspase - caspase 3 during MI through in silico tools. The protein-protein interaction network, QikProp, and molecular docking studies were performed to identify the lead compound that revealed Epicatechin Gallate (ECG) of COC as an effective inhibitor against candidate MI/apoptosis mediator - caspase 3. The docked complex was further taken for molecular dynamics simulation, which was achieved through Desmond. Molecular dynamics further confirmed the stability of the binding interactions between the docked complex. The overall in silico results proved that ECG could prevent the dissociation of cleaved caspases, which is essential for their activation. Computational observations were strongly supported by experimental evidence obtained from in vivo studies in the MI-model system. From the above observations, it was concluded that computational analysis was in good agreement with the experimental analysis on ECG's potential to prevent caspase 3 activation during MI.

Role of MicroRNAs in the Progression and Metastasis of Colon Cancer.

MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours, while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn's disease and Ulcerative colitis, which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc, will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

Ameliorative role of ellagic acid against acute liver steatosis in adult zebrafish experimental model.

Non-alcoholic fatty liver disease (NAFLD), also known as hepatic steatosis, is highly prevalent in developed countries despite advancements in clinical modalities. Therefore, there is a need for identifying the bioactive molecular entity (BME) that can therapeutically intervene with liver steatosis progression. In this study, we investigated the efficacy of one such BME - ellagic acid (EA) to ascertain its molecular therapeutic potential against iodoacetamide (IAA) mediated liver steatosis in an adult zebrafish model. Dysregulation of lipid homeostasis by IAA and its amelioration by EA was examined by histological staining and biochemical analysis in the adult zebrafish model. Furthermore, the gene expression analysis of 3-hydroxy methyl glutaryl (HMG) CoA reductase, fatty acid synthase and sterol receptor binding protein-1c in IAA mediated liver steatosis and its regulation by EA was also studied by reverse transcription-polymerase chain reaction (RT-PCR). Concurrently, the drug likeliness and pharmacokinetic properties of EA in comparison to Simvastatin (SIM) were analysed computationally by absorption, distribution, metabolism, and excretion (ADME) analysis. Also, the atomic level interactions of HMG-CoA reductase binding pocket with EA in comparison to SIM were examined by the molecular docking approach to ascertain their comparative binding energy (ΔG) and binding pose. Molecular docking revealed prominent hotspot residues (Gly 765, Gln 766, Asp 767, Gly 808) key to both EA and SIM interaction. All the above results revealed that the experimental observations wherein good agreement with the computational analysis substantiating the promising therapeutic potential of EA against IAA mediated liver steatosis.

Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression.

Quercetin is a bioactive compound with anti-inflammatory, antioxidant and anticancer properties. This study exemplifies the differential cytotoxic activity of Quercetin on two human colonic cancer cell lines, HT29 and HCT15. IC50 of Quercetin for HT29 and HCT15 cells were 42.5 µM and 77.4 µM, respectively. Activation of caspase-3, increased level of cytosolic cytochrome c, decreased levels of pAkt, pGSK-3ß and cyclin D1 in 40 µM Quercetin treated HT29 cells alone. Though, nuclear translocation of NFkB was increased in 40 µM Quercetin treated HT29 and HCT15 cells, over expression of COX-2 was observed in 40 µM Quercetin treated HT29 cells, whereas, Quercetin treated HCT15 cells did not expressed COX-2. Increased generation of reactive oxygen species (ROS) was observed only in Quercetin treated HT29 cells, which is due to over expression of COX-2, as COX-2 silencing inhibited Quercetin induced apoptosis and ROS generation. Insilico analysis provided evidence that Quercetin could partially inhibit COX-2 enzyme by binding to subunit A which has peroxidase activity and serves as source of ROS. However, Quercetin showed minimal effect on normal intestinal epithelial cells i,e IEC-6. To conclude, differential sensitivity of two cancer cells, HT29 and HCT15, to Quercetin depends on COX-2 dependent ROS generation that induces apoptosis and inhibits cell survival.