Differential Signaling Pathways in Medulloblastoma: Nano-biomedicine Targeting Non-coding Epigenetics to Improve Current and Future Therapeutics.

BACKGROUND: Medulloblastomas (MDB) are malignant, aggressive brain tumors that primarily affect children. The survival rate for children under 14 is approximately 72%, while for ages 15 to 39, it is around 78%. A growing body of evidence suggests that dysregulation of signaling mechanisms and noncoding RNA epigenetics play a pivotal role in this disease. METHODOLOGY: This study conducted an electronic search of articles on websites like PubMed and Google. The current review also used an in silico databases search and bioinformatics analysis and an extensive comprehensive literature search for original research articles and review articles as well as retrieval of current and future medications in clinical trials. RESULTS: This study indicates that several signaling pathways, such as sonic hedgehog, WNT/ß-catenin, unfolded protein response mediated ER stress, notch, neurotrophins and TGF-ß and ERK, MAPK, and ERK play a crucial role in the pathogenesis of MDB. Gene and ncRNA/protein are also involved as an axis long ncRNA to sponge micro-RNAs that affect downstream signal proteins expression and translation affection disease pathophysiology, prognosis and present potential target hit for drug repurposing. Current treatment options include surgery, radiation, and chemotherapy; unfortunately, the disease often relapses, and the survival rate is less than 5%. Therefore, there is a need to develop more effective treatments to combat recurrence and improve survival rates. CONCLUSION: This review describes various MDB disease hallmarks, including the signaling mechanisms involved in pathophysiology, related-causal genes, epigenetics, downstream genes/epigenes, and possibly the causal disease genes/non-protein coding (nc)RNA/protein axis. Additionally, the challenges associated with MDB treatment are discussed, along with how they are being addressed using nano-technology and nano-biomedicine, with a listing of possible treatment options and future potential treatment modalities.

Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling.

ß-catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating ß-catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting ß-catenin expression and its downregulatory signals, Cyclin D1, c-Myc. MLT + AGP treated cells exhibited translocation of phospho-ß-catenin to the nucleus and dephosphorylated-ß-catenin. Downregulation of ß-catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and ß-catenin found increased apoptosis and downregulation of ß-catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/ß-catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.

Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method.

Colorectal cancer (CRC) mortality has diminished for decades due to new and improved treatment profiles. However, CRC still ranks as the third most diagnosed cancer in the US. Therefore, a new therapeutic approach is needed to overcome colospheroids inhibition and drug resistance. It is well documented that andrographolide (AGP) and melatonin (MLT) have anti-carcinogenic properties. Our goal was to evaluate their synergistic effects on metastatic colon cancer cells (mCRC) and colospheroids. HT-29 and HCT-15 mCRC cells were simultaneously treated with serial dilutions of AGP and MLT for 24, 48 and 72 h. Cell viability was monitored using the MTT assay. The Chou-Talalay method for drug combination is based on the median effect equation, providing a theoretical basis for the combination index and the isobologram equation. This allows quantitative determination of drug interactions using the CompuSyn software, where CI < 1, = 1, and >1 indicates synergistic, additive, and antagonistic effects respectively. Our results demonstrate that AGP and MLT in combination show synergism with CI values of 0.35293 and 0.34152 for HT-29 and HCT-15 respectively and a fractional inhibition of Fa = 0.50-0.90, as shown by the Fa-CI plot and isobologram. The synergism value was validated in colospheroids (HT-29-s and HCT-15-s) based on morphology, viability, and colony formation and in 5-FU drug resistant cell (HT-29R and HCT-116R) viability. The mechanism(s) of decreased cell viability are due to the induction of ER stress proteins and angiogenic inhibition. Our results provide rationale for using AGP in combination with MLT on mCRC.