Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis.

Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary.

Canonical DDR activation by EMT inducing agent 5-Fluorouracil is modulated by a cannabinoid based combinatorial approach via inducing autophagy and suppression of vimentin expression.

Anastasis cascade including induction of Epithelial to Mesenchymal Transition (EMT), DNA repair, and stimulation of pro-survival mediators collectively exaggerate therapy resistance in cancer prognosis. The extensive implications of DNA-damaging agents are clinically proven futile for the rapid development of disease recurrence during treatment regime. Herein we report a glycosidic derivative of Δ9-tetrahydrocannabinol (THC-9-OG) abrogates sub-toxic doses of 5-Fluorouracil (5FU) induced EMT in colon cancer cells nullifying DNA repairing mechanism.

MicroRNA signatures differentiate types, grades, and stages of breast invasive ductal carcinoma (IDC): miRNA-target interacting signaling pathways.

Background: Invasive ductal carcinoma (IDC) is the most common form of breast cancer which accounts for 85% of all breast cancer diagnoses. Non-invasive and early stages have a better prognosis than late-stage invasive cancer that has spread to lymph nodes. The involvement of microRNAs (miRNAs) in the initiation and progression of breast cancer holds great promise for the development of molecular tools for early diagnosis and prognosis.

Retinoblastoma: present scenario and future challenges.

With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology.

Combinatorial therapy using RNAi and curcumin nano-architectures regresses tumors in breast and colon cancer models.

Cancer is a debilitating disease and one of the leading causes of death in the world. In spite of the current clinical management being dependent on applying robust pathological variables and well-defined therapeutic strategies, there is an imminent need for novel and targeted therapies with least side effects. RNA interference (RNAi) has gained attention due to its precise potential for targeting multiple genes involved in cancer progression.

Inulin coated MnO nanocuboids coupled with RNA interference reverse intestinal tumorigenesis in Apc knockout murine colon cancer models.

This study reports the development and pre-clinical evaluation of biodrug using RNA interference and nanotechnology. The major challenges in achieving targeted gene silencing in vivo include the stability of RNA molecules, accumulation into pharmacological levels, and site-specific targeting of the tumor. We report the use of Inulin for coating the arginine stabilized manganese oxide nanocuboids (MNCs) for oral delivery of shRNA to the gut.

Quantitative proteome profiling stratifies fibroepithelial lesions of the breast.

Breast fibroepithelial lesions (FELs) include heterogeneous pathological tumors, involving indolent fibroadenoma (FAD) to potentially aggressive phyllodes tumors (PTs). The current grading system remains unreliable in differentiating these tumors due to histological heterogeneity and lack of appropriate markers to monitor the sudden and unpredictable malignant transformation of PTs. Thus, there exists an imminent need for a marker-based diagnostic approach to augment the conventional histological platform that could lead to accurate diagnosis and distinction of FELs.

MicroRNA Signatures in Blood or Bone Marrow Distinguish Subtypes of Pediatric Acute Lymphoblastic Leukemia.

OncomiRs are microRNAs that are associated with early onset of specific cancers. To identify microRNAs involved in pediatric acute lymphoblastic leukemia (ALL) subtypes T-ALL and B-ALL, peripheral blood and bone marrow samples were independently subjected to microarray analysis using two different high-fidelity array platforms. The unique and common gene signatures from both arrays were validated by TaqMan individual assays in 100 pediatric ALL samples.

LeukmiR: a database for miRNAs and their targets in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies in children. Recent studies suggest the involvement of multiple microRNAs in the tumorigenesis of various leukemias. However, until now, no comprehensive database exists for miRNAs and their cognate target genes involved specifically in ALL.

EMT in breast cancer metastasis: an interplay of microRNAs, signaling pathways and circulating tumor cells.

Epithelial to Mesenchymal Transition (EMT) is a biological process characterized by the transition from immotile epithelial cells to motile mesenchymal cells. Though shown to be implicated in many biological processes, it has also been identified to enhance migration and invasion of cancer cells leading to metastasis. A class of microRNAs called "oncomiRs" plays a significant role in the regulation of malignant transformation and metastasis.

Vimentin activation in early apoptotic cancer cells errands survival pathways during DNA damage inducer CPT treatment in colon carcinoma model.

Epithelial to mesenchymal transitions (EMT) is a preparatory process for cancer cells to attain motility and further metastasis to distant sites. Majority of DNA damaging drugs have shown to develop EMT as one of the major mechanisms to attain drug resistance. Here we sought to understand the resistance/survival instincts of cancer cells during initial phase of drug treatment.

Biodrug Suppresses Breast and Colorectal Cancer in Murine Models.

RNA interference (RNAi) remains one of the most promising and emerging strategies for the effective cancer treatment due to its high target specificity and greater potency. However, it is hindered due to lack of appropriate targeting technologies. Therefore, there is an imminent need to develop specific and robust delivery systems for successful gene silencing.

Inhibition of Twist1-mediated invasion by Chk2 promotes premature senescence in p53-defective cancer cells.

Twist1, a basic helix-loop-helix transcription factor is implicated as a key mediator of epithelial-mesenchymal transition (EMT) and metastatic dissemination in p53-deficient cancer cells. On the other hand, checkpoint kinase 2 (Chk2), a major cell cycle regulatory protein provides a barrier to tumorigenesis due to DNA damage response by preserving genomic stability of the cells. Here we demonstrate that Chk2 induction proficiently abrogates invasion, cell scattering and invadopodia formation ability of p53-mutated invasive cells by suppressing Twist1, indicating Chk2 confers vital role in metastasis prevention.

Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E.

The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz.

Par-4 dependent modulation of cellular β-catenin by medicinal plant natural product derivative 3-azido Withaferin A.

Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating β-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear β-catenin and augmented its cytoplasmic pool as evidenced by reducing β-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3β (by Akt) to promote β-catenin destabilization.

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells.

An active medicinal component of plant origin with an ability to overcome autophagy by inducing apoptosis should be considered a therapeutically active lead pharmacophore to control malignancies. In this report, we studied the effect of concentration-dependent 3-AWA (3-azido withaferin A) sensitization to androgen-independent prostate cancer (CaP) cells which resulted in a distinct switching of 2 interrelated conserved biological processes, i.e.

RNA Interference Using c-Myc-Conjugated Nanoparticles Suppresses Breast and Colorectal Cancer Models.

In this article, we report the development and preclinical validation of combinatorial therapy for treatment of cancers using RNA interference (RNAi). RNAi technology is an attractive approach to silence genes responsible for disease onset and progression. Currently, the critical challenge facing the clinical success of RNAi technology is in the difficulty of delivery of RNAi inducers, due to low transfection efficiency, difficulties of integration into host DNA and unstable expression.

OncomiRdbB: a comprehensive database of microRNAs and their targets in breast cancer.

Background: Given the estimate that 30% of our genes are controlled by microRNAs, it is essential that we understand the precise relationship between microRNAs and their targets. OncomiRs are microRNAs (miRNAs) that have been frequently shown to be deregulated in cancer. However, although several oncomiRs have been identified and characterized, there is as yet no comprehensive compilation of this data which has rendered it underutilized by cancer biologists.

Gene manipulation through the use of small interfering RNA (siRNA): from in vitro to in vivo applications.

The conventional approach to investigate genotype-phenotype relationships has been the generation of gene targeted murine strains. However, the emergence of RNAi technologies has opened the possibility of much more rapid (and indeed more cost effective) genetic manipulation in vivo at the level of the transcriptome. Successful application of RNAi in vivo depends on intracellular targeted delivery of siRNA/shRNA molecules for efficient knockdown of the desired gene.