A novel combinatorial approach using sulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.

Targeting cancer epigenetics with CRISPR-dCAS9: Principles and prospects.

Cancer therapeutics is an ever-evolving field due to incessant demands for effective and precise treatment options. Over the last few decades, cancer treatment strategies have shifted somewhat from surgery to targeted precision medicine. CRISPR-dCas9 is an emerging version of precision cancer therapy that has been adapted from the prokaryotic CRISPR-Cas system. Once ligated to epigenetic effectors (EE), CRISPR-dCas9 can function as an epigenetic editing tool and CRISPR-dCas9-EE complexes could be exploited to alter cancerous epigenetic features associated with different cancer hallmarks. In this article, we discuss the rationale of epigenetic editing as a therapeutic strategy against cancer. We also outline how sgRNA-dCas9 was derived from the CRISPR-Cas system. In addition, the current status of sgRNA-dCas9 use (in vivo and in vitro) in cancer is updated with a molecular illustration of CRISPR-dCas9-mediated epigenetic and transcriptional modulation. As sgRNA-dCas9 is still at the developmental phase, challenges are inherent to its use. We evaluate major challenges in targeting cancer with sgRNA-dCas9 such as off-target effects, lack of sgRNA designing rubrics, target site selection dilemmas and deficient sgRNA-dCas9 delivery systems. Finally, we appraise the sgRNA-dCas9 as a prospective cancer therapeutic by summarizing ongoing improvements of sgRNA-dCas9 methodology.

MicroRNAs and Epigenetics Strategies to Reverse Breast Cancer.

Breast cancer is a sporadic disease with genetic and epigenetic components. Genomic instability in breast cancer leads to mutations, copy number variations, and genetic rearrangements, while epigenetic remodeling involves alteration by DNA methylation, histone modification and microRNAs (miRNAs) of gene expression profiles. The accrued scientific findings strongly suggest epigenetic dysregulation in breast cancer pathogenesis though genomic instability is central to breast cancer hallmarks. Being reversible and plastic, epigenetic processes appear more amenable toward therapeutic intervention than the more unidirectional genetic alterations. In this review, we discuss the epigenetic reprogramming associated with breast cancer such as shuffling of DNA methylation, histone acetylation, histone methylation, and miRNAs expression profiles. As part of this, we illustrate how epigenetic instability orchestrates the attainment of cancer hallmarks which stimulate the neoplastic transformation-tumorigenesis-malignancy cascades. As reversibility of epigenetic controls is a promising feature to optimize for devising novel therapeutic approaches, we also focus on the strategies for restoring the epistate that favor improved disease outcome and therapeutic intervention.

Evaluation of Hymenodictyon excelsum Phytochemical's Therapeutic Value Against Prostate Cancer by Molecular Docking Study.

BACKGROUND: Hymenodictyon excelsum is a medicinal plant traditionally used for tumor treatment as it contains phytochemicals of anthraquinone and coumarin class. OBJECTIVES: The aim of the present study was to unfold the therapeutic value of selected phytocompounds of Hymenodictyon excelsum in prostate cancer. MATERIALS AND METHODS: Eight phytochemicals were selected based on the literature search including anthragallol, damnacanthal, esculin, lucidin, morindone, nordamnacanthal, rubiadin, and soranjidiol while dihydrotestosterone was considered as the control. Human androgen receptor (AR) ligand binding domain (PDB id: 1e3g) was selected as the receptor for subsequent computational docking study. First, the selected phytocompounds were screened for their drug likeness and safety profile. Molegro Virtual Docker (MVD) was subjected only to drug-like and safe phytocompounds for the computational docking study. RESULTS: Except for anthragallol, nordamnacanthal and rubiadin, all the ligands were drug-like and safe. Results of the docking study suggest a favorable binding of esculin to the receptor with respect to dihydrotestosterone. Analysis of docking pattern revealed a nearly similar ligand-receptor interaction for both dihydrotestosterone and esculin. CONCLUSIONS: The anthraquinone and coumarin principles of H. excelsum have an anti-prostate cancer effect that has been proposed to be exerted by antagonistic effects on AR.

A review on Ipomoea carnea: pharmacology, toxicology and phytochemistry.

Phytomedicines are increasingly being established in modern medical science. The shrub Ipomoea carnea has been used traditionally for thousands of years. However, there are few scientific studies on this medicinal plant, and most of the information are scattered. In this review, we have summarized the existing knowledge and recent progress on the medicinal importance of I. carnea. Different extracts of I. carnea plant possess anti-bacterial, anti-fungal, anti-oxidant, anti-cancer, anti-convulsant, immunomodulatory, anti-diabetic, hepatoprotective, anti-inflammatory, anxiolytic, sedative and wound healing activities. However, some toxicological effects have been also reported. Some of the major phytochemicals associated with the bioactivity of I. carnea have been characterized, which have been discussed in this study too. This review article might be beneficial for phytotherapy research, as I. carnea can be a good source for drug development.

Hericium erinaceus: an edible mushroom with medicinal values.

Mushrooms are considered as nutritionally functional foods and source of physiologically beneficial medicines. Hericium erinaceus, also known as Lion's Mane Mushroom or Hedgehog Mushroom, is an edible fungus, which has a long history of usage in traditional Chinese medicine. This mushroom is rich in some physiologically important components, especially ß-glucan polysaccharides, which are responsible for anti-cancer, immuno-modulating, hypolipidemic, antioxidant and neuro-protective activities of this mushroom. H. erinaceus has also been reported to have anti-microbial, anti-hypertensive, anti-diabetic, wound healing properties among other therapeutic potentials. This review article has overviewed the recent advances in the research and study on H. erinaceus and discussed the potential health beneficial activities of this mushroom, with the recognition of bioactive compounds responsible for these medicinal properties.