Analysis of Inhibition Potential of Nimbin and its Analogs against NF-κB Subunits P50 and P65: A Molecular Docking and Molecular Dynamics Study.

BACKGROUND: Cancer remains the major cause of morbidity and mortality. The nuclear factor kappa-B (NF-κB) plays an indispensable role in cancer cell proliferation and drug resistance. The role of NF-κB is not only limited to tumor cell proliferation and suppression of apoptotic genes but it also induces EMT transition responsible for metastasis. Inhibition of the NF-κB pathway in cancer cells by herbal derivatives makes it a favorable yet promising target for cancer therapeutics. AIM: The purpose of the study is to explore the inhibition potential of Nimbin and its analogs against NF-κB subunits p50 and p65. METHODS: In the present study, an herbal compound Nimbin and its derivative analogs were investigated to examine their impact on the p50 and p65 subunits of the NF-κB signaling pathway using in-silico tools, namely molecular docking and simulation. RESULTS: The molecular docking analysis revealed that Nimbin and its analogs may bind to p50 and p65 subunits with dG bind values ranging from -33.23 to -50.49Kcal/mol. Interestingly, molecular dynamic simulation for the NO5-p65 complex displayed a stable conformation and convergence when compared to the NO4-p50 complex. CONCLUSION: These results indicate that NO5 may have a potential inhibitory effect against NF-κB subunit p65, which needs to be further validated in in-vitro and in-vivo systems. Also, the results obtained emphasize and pave the way for exploring the Nimbin scaffold against NF-κB inhibition for cancer therapeutics.

Liquid Biopsies: Emerging role and clinical applications in solid tumours.

Late detection and lack of precision diagnostics are the major challenges in cancer prevention and management. Biomarker discovery in specific cancers, especially at the pre-invasive stage, is vital for early diagnosis, positive treatment response, and good disease prognosis. Traditional diagnostic measures require invasive procedures such as tissue excision using a needle, an endoscope, and/or surgical resection which can be unsafe, expensive, and painful. Additionally, the presence of comorbid conditions in individuals might render them ineligible for undertaking a tissue biopsy, and in some cases, it is difficult to access tumours depending on the site of occurrence. In this context, liquid biopsies are being explored for their clinical significance in solid malignancies management. These non-invasive or minimally invasive methods are being developed primarily for identification of biomarkers for early diagnosis and targeted therapeutics. In this review, we have summarised the use and importance of liquid biopsy as significant tool in diagnosis, prognosis prediction, and therapeutic development. We have also discussed the challenges that are encountered and future perspective.

Mitochondrial DNA content as a biomarker for oral carcinogenesis: correlation with clinicopathologic parameters.

BACKGROUND: Mitochondrial genome (mtDNA) exhibits greater vulnerability to mutations and/or copy number variations than nuclear counterpart (nDNA) in both normal and cancer cells due to oxidative stress generated by inflammation, viral infections, physical, mechanical, and chemical load. The study was designed to evaluate the mtDNA content in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC). Various parameters were analyzed including its variation with human papillomavirus (HPV) during oral carcinogenesis. METHODS: The present cross-sectional study comprised of two hundred patients (100 OPMDs and 100 OSCCs) and 100 healthy controls. PCR amplifications were done for mtDNA content and HPV in OPMDs and OSCC using real-time and conventional PCR respectively. RESULTS: The relative mtDNA content was assessed quantitatively and it was observed that mtDNA was greater in OSCC (7.60±0.94) followed by OPMDs (5.93±0.92) and controls (5.37±0.95). It showed a positive linear correlation with habits and increasing histopathological grades. Total HPV-positive study groups showed higher mtDNA content (7.06±1.64) than HPV-negative counterparts (6.21±1.29). CONCLUSIONS: An elevated mutant mtDNA may be attributed to increased free radicals and selective cell clonal proliferation in test groups. Moreover, sustained HPV infection enhances tumorigenesis through mitochondria mediated apoptosis. Since, mtDNA content is directly linked to oxidative DNA damage, these quantifications might serve as a surrogate measure for invasiveness in dysplastic lesions and typify their malignant potential.

Molecular basis of epigenetic regulation in cancer diagnosis and treatment.

The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.

Insights into the role of complement regulatory proteins in HPV mediated cervical carcinogenesis.

The persistent infection of high-risk Human papillomavirus (HR-HPV) induced cervical cancer remains a challenge in women worldwide including India. Recent advances in cancer research have paved the way for advanced cancer treatment modalities including immunotherapy by manipulating the function or number of cytotoxic T cells. It is well established that anaphylatoxins like C3a and C5a of complement system influence tumor growth by evading apoptosis leading to progression of cancer. The role of the complement system, particularly the complement regulatory proteins (CRPs) which are important determinants of immune response play a crucial role in carcinogenesis. In a tumor microenvironment (TME) assisted suppression of immune effector cells may be achieved through CRPs. However, recent advances in pharmacogenomics including drug designing and combination of these approaches have provided a holistic understanding of signaling pathways and their crosstalk, to regulate cellular communications.This review describes the role of complement system; particularly CRPs in HPV induced cervical carcinogenesis which may be used for designing anti- HPV or cervical cancer therapeutics.

Role of epigenetics in carcinogenesis: Recent advancements in anticancer therapy.

The role of epigenetics in the etiology of cancer progression is being emphasized for the past two decades to check the impact of chromatin modifiers and remodelers. Histone modifications, DNA methylation, chromatin remodeling, nucleosome positioning, regulation by non-coding RNAs and precisely microRNAs are influential epigenetic marks in the field of progressive cancer sub-types. Furthermore, constant epigenetic changes due to hyper or hypomethylation could efficiently serve as effective biomarkers of cancer diagnosis and therapeutic development. Ongoing research in the field of epigenetics has resulted in the resolutory role of various epigenetic markers and their inhibition using specific inhibitors to arrest their key cellular functions in in-vitro and pre-clinical studies. Although, the mechanism of epigenetics in cancer largely remains unexplored. Nevertheless, various advancements in the field of epigenetics have been made through transcriptome analysis and in-vitro genome targeting technologies to unravel the applicability of epigenetic markers for future cancer therapeutics and management. Therefore, this review emphasizes on recent advances in epigenetic landscapes that could be targeted/explored using novel approaches as personalized treatment modalities for cancer containment.

Exosomes: A Forthcoming Era of Breast Cancer Therapeutics.

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.

Cancer immunotherapy: a promising dawn in cancer research.

Cancer is a highly proliferative disease, which is caused due to the loss of regulation of cell cycle and apoptosis, DNA damage, faulty repair system etc. The cancer microenvironment plays a pivotal role in disease progression as they contain different types of innate and adaptive immune cells. The most important molecules that establish a correlation between inflammation, innate immunity, adaptive immunity, and cancer are the molecules released by inflammatory cells in cancer microenvironment. These molecules secreted by the immune cells, which might activate a pro-tumorigenic and anti-tumorigenic response in cancer. In inflammatory microenvironment, the equilibrium state of immunosuppressive and immunostimulatory signals are important in tumor suppression. The immunotherapeutic approaches could be more effective in cancer treatment. However, advancement in immunobiology and cancer are improving the prospects of immunotherapy alone and/or in combination with the conventional therapies. Thus, the review attempts to highlight a promising and futuristic immunotherapeutic approach in combination with conventional treatment modalities.