Polymolecular botanical drug of Orthosiphon stamineus extract (C5OSEW5050ESA) as a complementary therapy to overcome gemcitabine resistance in pancreatic cancer cells.

Background and aim: Gemcitabine remains the cornerstone of pancreatic cancer treatment, despite exhibiting a modest effect on patient survival due to the development of drug resistance. Nuvastatic™ polymolecular botanical drug Orthosiphon stamineus (O. stamineus) is a folklore Asian herbal medicine that is used for the treatment of a variety of ailments. However, little is known about the mechanism of actions of the Nuvastatic™ polymolecular botanical drug of O. stamineus as a complementary therapy in resistant pancreatic cancer. It is postulated that the proprietary O. stamineus extract formulation (ID: C5EOSEW5050ESA) in Nuvastatic™ may sensitise resistant pancreatic cancer cells to gemcitabine. This study was conducted to assess the cytotoxic activity and synergistic effects of C5EOSEW5050ESA in gemcitabine-resistant pancreatic cancer cells. Experimental procedure: The effects of C5EOSEW5050ESA treatment on cell viability, multidrug-resistant genes, epithelial-mesenchymal transition, cellular senescence, cell death, and Notch signalling pathway were evaluated in gemcitabine-resistant Panc-1 cells. Results and conclusion: C5EOSEW5050ESA sensitised gemcitabine resistant cells towards C5EOSEW5050ESA-gemcitabine combination treatment by reducing the expression of multidrug-resistant genes and epithelial-mesenchymal transition markers in gemcitabine-resistant cells compared to the control group, possibly through the inhibition of Notch signalling. This study provides valuable insight into using C5EOSEW5050ESA as a potential complementary treatment for resistant pancreatic cancer.

Complementary effects of Orthosiphon stamineus standardized ethanolic extract and rosmarinic acid in combination with gemcitabine on pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.s) is used widely as a traditional medicine for the treatment of multiple ailments, including cancer in South East Asia. The present in vitro study was designed to investigate the complementary effects of an ethanolic extract of O.s (Et. O.s) or rosmarinic acid in combination with gemcitabine on Panc-1 pancreatic cancer cells. METHOD: Cell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC50) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry. RESULTS: Et. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain. CONCLUSION: This study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.

Potential role of marine species-derived bioactive agents in the management of SARS-CoV-2 infection.

COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material obtained from marine species, including griffithsin, plitidepsin and fingolimod are in clinical trials to evaluate their anti-SARS-CoV-2 and anti-HIV efficacies. The current review highlights the anti-SARS-CoV-2 potential of marine-derived phytochemicals explored using in silico, in vitro and in vivo models. The current literature suggests that these molecules have the potential to bind with various key drug targets of SARS-CoV-2. In addition, many of these agents have anti-inflammatory and immunomodulatory potentials and thus could play a role in the attenuation of COVID-19 complications. Overall, these agents may play a role in the management of COVID-19, but further preclinical and clinical studies are still required to establish their role in the mitigation of the current viral pandemic.

Toxicological studies of Orthosiphon stamineus (Misai Kucing) standardized ethanol extract in combination with gemcitabine in athymic nude mice model.

Pancreatic cancer has the highest mortality rate among cancers due to its aggressive biology and lack of effective treatment. Gemcitabine, the first line anticancer drug has reduced efficacy due to acquired resistance. The current study evaluates the toxicological effects of Orthosiphon stamineus (O.s) and its marker compound (rosmarinic acid) in combination with gemcitabine. O.s (200 or 400 mg/kg/day) and rosmarinic acid (32 mg/kg/day) were administered orally and gemcitabine (10 mg/kg/3 days) intraperitoneally either alone or in combination treatment for fourteen days. Parameters including blood serum biochemistry, hematology, myeloid-erythroid ratio, incident of lethality, and histopathological analysis of liver, kidney, and spleen tissues were studied. Neither, individual drugs/extract nor chemo-herbal combinations at tested doses induced any toxicity and damage to organs in nude mice when compared to control group. Toxicological data obtained from this study will help to select the best doses of chemo-herbal combination for future pancreatic xenograft tumor studies.

MicroRNA pathways: an emerging role in identification of therapeutic strategies.

For years researchers have exerted every effort to improve the influential roles of microRNA (miRNA) in regulating genes that direct mammalian cell development and function. In spite of numerous advancements, many facets of miRNA generation remain unresolved due to the perplexing regulatory networks. The biogenesis of miRNA, eminently endures as a mystery as no universal pathway defines or explicates the variegation in the rise of miRNAs. Early evidence in biogenesis ignited specific steps of being omitted or replaced that eventuate in the individual miRNAs of different mechanisms. Understanding the basic foundation concerning how miRNAs are generated and function will help with diagnostic tools and therapeutic strategies. This review encompasses the canonical and the non-canonical pathways involved in miRNA biogenesis, while elucidating how miRNAs regulate genes at the nuclear level and also the mechanism that lies behind circulating miRNAs.