Research/Publications

Casticin Impacts Key Signaling Pathways in Colorectal Cancer Cells Leading to Cell Death with Therapeutic Implications

Colorectal cancer is the third most frequently encountered cancer worldwide. While current chemotherapeutics help to manage the disease to some extent, they have eluded achieving complete remission and are limited by their severe side effects. This warrants exploration of novel agents that are efficacious with anticipation of minimal adverse effects. In the current study, casticin, a tetramethoxyflavone, was tested for its ability to inhibit the viability of three human colorectal cancer cells: adenocarcinoma (DLD-1, Caco-2 cell lines) and human colorectal carcinoma cells (HCT116 cell line). Casticin showed potent inhibition of viability of DLD-1 and HCT116 cells. Clonogenic assay performed in DLD-1 cells revealed that casticin impeded the colony-forming efficiency of the cells, suggesting its impact on the proliferation of these cells. Further, a sustained effect of the inhibitory action upon withdrawal of the treatment was observed. Elucidation of the mechanism of action revealed that casticin impacted the extrinsic programmed cell death pathway, leading to an increase in apoptotic cells. Further, Bcl-2, the key moiety of cell survival, was affected. Notably, a significant number of cells were arrested in the G2/M phase of the cell cycle in DLD-1 cells. Due to the multifaceted action of casticin, we envision that treatment with casticin could provide an efficacious treatment option for colorectal adenocarcinomas with minimal side effects.

Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy

Abstract

The prevalence of colorectal cancer has increased world-wide with high rates of mortality and morbidity. In the absence of efficacious drugs to treat this neoplasia, there is an imminent need to discover molecules with multifaceted effects. To this end, we opted to study the effect of steroidal saponins such as Polyphyllins. We performed anticancer activity studies with three analogs of Polyphyllins: Polyphyllin D (PD), Polyphyllin II (PII) and Polyphyllin G (PG). Here we show the potent effect of PD, PII (IC50 of 0.5−1 µM) and PG (IC50 of 3 µM) in inhibiting the viability of colorectal adenocarcinoma cells (DLD-1) and colorectal carcinoma cells (HCT116). PD and PII also showed inhibition of cell proliferation and sustained response upon withdrawal of the compounds when assessed by clonogenic assays in both the cell lines. Elucidation of the molecular mode of action revealed impact on the programmed cell death pathway. Additionally, proteomic profiling of DLD-1 revealed pivotal proteins differentially regulated by PD and PII, including a downregulated peroxiredoxin-1 which is considered as one of the novel targets to combat colorectal cancers and an upregulated elongation factor 2 (EF2), one of the key molecules considered as a tumor associated antigen (TAA) in colon cancer. Entities of cell metabolic pathways including downregulation of the key enzyme Phosphoglycerate kinase 1 of the glycolytic pathway was also observed. Importantly, the fold changes per se of the key components has led to the loss of viability of the colorectal cancer cells. We envision that the multifaceted function of PD and PII against the proliferation of colorectal carcinoma cells could have potential for novel treatments such as chemoimmunotherapy for colorectal adenocarcinomas. Future studies to develop these compounds as potent anti-colorectal cancer agents are warranted.

https://www.mdpi.com/2227-9059/10/3/583/htm


Computational Identification of Stearic Acid as a Potential PDK1 Inhibitor and In Vitro Validation of Stearic Acid as Colon Cancer Therapeutic in Combination with 5-Fluorouracil

Abstract


Interception of Signaling Circuits of Esophageal Adenocarcinoma Cells by Resveratrol Reveals Molecular and Immunomodulatory Signatures

Deregulation of signaling pathways due to mutations sets the cell on a path to neoplasia. Therefore, recent reports of increased mutations observed in esophageal tissue reflects the enhanced risk of tumor formation. In fact, adenocarcinoma of the esophagus has been on the rise lately. Increase in mortality due to a paucity of efficacious drugs for this cancer prompted us to discover molecular signatures to combat this malady. To this end, we chose resveratrol—a polyphenol with anticancer property—and studied its impact on three esophageal adenocarcinoma cell lines (OE33, OE19 and FLO-1) by multilevel profiling. Here, we show the impact of resveratrol on the viability of the three adenocarcinoma esophageal cell systems studied, at the cellular level. Furthermore, an analysis at the molecular level revealed that the action was through the programmed cell death pathway, resulting in an increase in apoptotic and caspase-positive cells. The impact on reactive oxygen species (ROS) and a decrease in Bcl2 levels were also observed. Moreover, proteomic profiling highlighted pivotal differentially regulated signaling molecules. The phenotypic effect observed in resveratrol-treated esophageal cells could be due to the stoichiometry per se of the fold changes observed in entities of key signaling pathways. Notably, the downregulation of Ku80 and other pivotal entities by resveratrol could be harnessed for chemo-radiation therapy to prevent DNA break repair after radiation therapy. Additionally, multilevel profiling has shed light on molecular and immune-modulatory signatures with implications for discovering novel treatments, including chemo-immunotherapy, for esophageal adenocarcinomas which are known to be aggressive cancers.

Cellular molecular and proteomic profiling deciphers the SIRT1 controlled cell death pathways in esophageal adenocarcinoma cells

Abstract

Worldwide prevalence of esophageal adenocarcinomas with high rates of mortality coupled with increased mutations in esophageal cells warrants investigation to understand deregulation of cell signaling pathways leading to cancer. To this end, the current study was undertaken to unravel the cell death signatures using the model human esophageal adenocarcinoma cell line-OE33. The strategy involved targeting the key epigenetic modulator SIRT1, a histone deacetylase by a small molecule inhibitor – sirtinol. Sirtinol induced a dose-dependent inhibition of cell viability under both normoxic and hypoxic conditions with long term impact on proliferation as shown by clonogenic assays. Signature apoptotic signaling pathways including caspase activation and decreased Bcl-2 were observed. Proteomic analysis highlighted an array of entities affected including molecules involved in replication, transcription, protein synthesis, cell division control, stress-related proteins, spliceosome components, protein processing and cell detoxification/degradation systems. Importantly, the stoichiometry of the fold changes of the affected proteins per se could govern the cell death phenotype by sirtinol. Sirtinol could also potentially curb resistant and recurrent tumors that reside in hypoxic environments. Overall, in addition to unraveling the cellular, molecular and proteomics basis of SIRT1 inhibition, the findings open up avenues for designing novel strategies against esophageal adenocarcinoma.

https://www.sciencedirect.com/science/article/pii/S2468294220301064


Inhibition of Prostate Cancer Cells by 4,5-Dicaffeoylquinic Acid through Cell Cycle Arrest

Abstract

Prostate cancer is a major cause of cancer-related mortality in men. Even though current therapeutic management has contributed to reducing mortality, additional intervention strategies are warranted to further improve the outcomes. To this end, we have investigated the efficacy of dicaffeoylquinic acids, ingredients in Yerba Mate (Ilex paraguariensis), an evergreen cultivated in South America, the leaves of which are used to prepare a tea/coffee-like drink. Of the various analogs tested, 4,5-dicaffeoylquinic acid (4,5-diCQA) was the most active molecule against DU-145 prostate cancer cells with a 50% inhibitory concentration (IC50) of 5 μM. 4,5-diCQA was active both under normoxic and hypoxic conditions. The effect of 72-hour treatment on DU-145 cells persisted for an extended time period as assessed by clonogenic assay. Mechanistic studies revealed that the toxic effect was not due to induction of programmed cell death but through cell cycle arrest at S phase. Additionally, 4,5-diCQA did not impact PI3K/MAPK signaling pathway nor did it affect the depolarization of the mitochondrial membrane. 4,5-diCQA-induced accumulation of cells in the S-phase also seems to negatively impact Bcl-2 expression. 4,5-diCQA also exhibited inhibitory activity on LNCaP and PC-3 prostate cancer cells suggesting that it has therapeutic potential on a broad range of prostate cancers. Taken together, the novel inhibitory activity and mechanism of action of 4,5-diCQA opens up potential therapeutic options for using this molecule as monotherapy as well as in combinatorial therapies for the clinical management of prostate cancer.

https://www.hindawi.com/journals/pc/2019/4520645/

—23 May 2019


KeenZineFighting the Big C with the 3 C’s

“Recently, I’ve made cancer the focus of Georgia Tech’s Quantitative Engineering Physiology Course. The global impact of this disease is clear and the recently launched “Cancer Moonshot” initiative makes it a timely topic. We challenge our students to own their laboratory experiences and engineer strategies to interfere with the physiological processes that lead to cancer. Student teams develop their own comprehensive research proposals, which then become the foundation for experimental validation in the lab and employing relevant techniques.”

—from KEENZine

http://online.fliphtml5.com/zyet/ykie/#p=31