Phytochemicals in cancer cell chemosensitization: Current knowledge and future perspectives.

Despite significant advancements made in the treatment of cancer during the past several decades, it remains one of the leading causes of death worldwide killing approximately 9.6 million people annually. The major challenge for therapeutic success is the development of chemoresistance in cancer cells against conventional chemotherapeutic agents via modulation of numerous survival and oncogenic signaling pathways. Therefore, sensitization of cancer cells to conventional drugs using multitargeted agents that suppress the survival and oncogenic pathways, in single or in combination, is an emerging strategy to overcome drug-resistance. During the last couple of decades, phytochemicals such as curcumin, resveratrol, tocotrienol and quercetin have emerged as potential chemosensitizing agents in cancer cells due to their less toxic and multitargeted properties. Numerous preclinical and clinical studies enumerated their potential to prevent drug resistance and sensitize cancer cells to chemotherapeutic agents by modulating several genes/proteins or pathways that regulate the key factors during the growth and progression of tumors such as inhibition of anti-apoptotic proteins, activation of pro-apoptotic proteins, reduced expression of different transcription factors, chemokines, enzymes, cell adhesion molecules, protein tyrosine kinases and cell cycle regulators. Therefore, natural chemosensitizing agents will have a special place in cancer treatment in the near future. This comprehensive review summarizes data obtained from various in vitro, in vivo and clinical studies to provide a new perspective for the application of agents obtained from "Mother Nature" as potential chemosensitizers for further cancer drug research and development.

Wogonin and its analogs for the prevention and treatment of cancer: A systematic review.

The medicinal plant Scutellaria baicalensis, commonly known as Chinese skullcap or Huang-Qin, has been used as a traditional medicine for several thousand years. The roots of this plant contain bioactive compounds, such as wogonin (WOG), wogonoside, baicalein, and baicalin. The aim of this article is to evaluate the therapeutic potential and mechanisms of action of WOG against different cancers. Numerous in vitro and in vivo studies have revealed that WOG exerts immense therapeutic potential against bladder cancer, breast cancer, cholangiocarcinoma, cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatic cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer by regulating various cell signaling pathways. WOG, in combination with established chemotherapeutic drugs, improves the efficacy of treatment and lowers toxicity. Nevertheless, human trials are warranted to validate these findings. Numerous preclinical studies, combined with an extensive margin of safety and no severe side effects, underscore WOG's therapeutic potential as an anticancer drug. These studies propound the use of WOG as a potential anticancer candidate; however, further high-quality studies are required to firmly establish the clinical efficacy of WOG for the prevention and treatment of human malignancies.

Inflammation, NF-κB, and Chronic Diseases: How are They Linked?

Most chronic diseases, caused by lifestyle factors, appear to be linked to inflammation. Inflammation is activated mechanistically, and nuclear factor-κB (NF-κB) is a significant mediator. NF-κB, one of the most studied transcription factors, was first identified in the nucleus of B lymphocytes almost three decades ago. This protein has a key function in regulating the human immune system, and its dysregulation has been linked to many chronic diseases including asthma, cancer, diabetes, rheumatoid arthritis, inflammation, and neurological disorders. Physiologically, many cytokines have been discovered that activate NF-κB. Pathologically, environmental carcinogens such as cigarette smoke, radiation, bacteria, and viruses can also activate this transcription factor. NF-κB activation controls expression of more than 500 genes, and most are deleterious to the human body when dysregulated. More than 70,000 articles have been published regarding NF-κB. This review emphasizes the upside and downside of NF-κB in normal and disease conditions and the ways in which we can control this critical transcription factor in patients.

Upside and Downside of Tumor Necrosis Factor Blockers for Treatment of Immune/Inflammatory Diseases.

Tumor necrosis factor (TNF)-α, the most potent proinflammatory cytokine discovered to date, was first isolated in 1984 from human macrophage cells. Initially, it was thought to be a protein that was cytotoxic to tumor cells. But later, it was regarded as an agent that promotes inflammation and other chronic diseases found in humans. Currently, we know that the TNF superfamily (TNFS) has 19 members that perform a wide variety of functions via > 40 TNF receptors. Of TNFS members, TNF-α has been studied extensively and was found to be implicated in numerous autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus, juvenile idiopathic arthritis, and diabetes. Thus, agents that can inhibit TNF-α have great potential for prevention and treatment of chronic diseases. To date, the U.S. Food and Drug Administration has approved many TNF-α blockers, such as etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. These agents can block TNF-α actions and be used to treat different diseases. However, the uses of TNF-α blockers are not without serious adverse effects. Therefore, natural TNF-α blockers are best for developing safe, efficacious, and affordable agents for prevention and treatment of chronic diseases. The current review details the TNFS, functions of TNF-α in normal and disease conditions, roles of TNF-α blockers, and advantages and disadvantages.

An Update on Pharmacological Potential of Boswellic Acids against Chronic Diseases.

Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri. It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson's disease, Alzheimer's, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.

Possible use of Punica granatum (Pomegranate) in cancer therapy.

The intake of fruits has proven to reduce the risk and incidence of cancer worldwide and plays a crucial role in cancer prevention. Pomegranate (Punica granatum), which belongs to the Punicaceae family, is one such plant that contains beneficial nutrients as well as many bioactive components and important phytochemicals that can be attributed to cancer-related therapeutic purposes. Pomegranate possesses antioxidant, anti-inflammatory, anti-proliferative, anti-angiogenic, anti-invasive, and anti-metastatic properties, and induces apoptosis. It also down-regulates various signaling pathways such as NF-κB, PI3K/AKT/mTOR, and Wnt, and down-regulates the expression of genes that are responsible in cancer development, such as anti-apoptotic genes, MMPs, VEGF, c-met, cyclins, Cdks, and pro-inflammatory cytokines. Therefore, inclusion of the fruit in one's diet would assist in a healthy life protected from cancer and also act as an effective chemotherapeutic with no toxic side effects.

Loss of TIPE3 reduced the proliferation, survival and migration of lung cancer cells through inactivation of Akt/mTOR, NF-κB, and STAT-3 signaling cascades.

Lung cancer is the foremost cause of cancer related mortality among men and one of the most fatal cancers among women. Notably, the 5-year survival rate of lung cancer is very low; 5% in developing countries. This low survival rate can be attributed to factors like late stage diagnosis, rapid postoperative recurrences in the patients undergoing treatment and development of chemoresistance against different agents used for treating lung cancer. Therefore, in this study we evaluated the potential of a recently identified protein namely TIPE3 which is known as a transfer protein of lipid second messengers as a lung cancer biomarker. TIPE3 was found to be significantly upregulated in lung cancer tissues indicating its role in the positive regulation of lung cancer. Supporting this finding, knockout of TIPE3 was also found to reduce the proliferation, survival and migration of lung cancer cells and arrested the G2 phase of cell cycle through inactivation of Akt/mTOR, NF-κB, STAT-3 signaling. It is well evinced that tobacco is the major risk factor of lung cancer which affects both males and females. Therefore, this study also evaluated the involvement of TIPE3 in tobacco mediated lung carcinogenesis. Notably, this study shows for the first time that TIPE3 positively regulates tobacco induced proliferation, survival and migration of lung cancer through modulation of Akt/mTOR signaling. Thus, TIPE3 plays critical role in the pathogenesis of lung cancer and hence it can be specifically targeted to develop novel therapeutic strategies.

The promising potential of piperlongumine as an emerging therapeutics for cancer.

In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.

A novel bioavailable curcumin-galactomannan complex modulates the genes responsible for the development of chronic diseases in mice: A RNA sequence analysis.

BACKGROUND: Chronic diseases or non-communicable diseases are a major burden worldwide due to the lack of highly efficacious treatment modalities and the serious side effects associated with the available therapies. PURPOSE/STUDY DESIGN: A novel self-emulsifying formulation of curcumin with fenugreek galactomannan hydrogel scaffold as a water-dispersible non-covalent curcumin-galactomannan molecular complex (curcumagalactomannosides, CGM) has shown better bioavailability than curcumin and can be used for the prevention and treatment of chronic diseases. However, the exact potential of this formulation has not been studied, which would pave the way for its use for the prevention and treatment of multiple chronic diseases. METHODS: The whole transcriptome analysis (RNAseq) was used to identify differentially expressed genes (DEGs) in the liver tissues of mice treated with LPS to investigate the potential of CGM on the prevention and treatment of chronic diseases. Expression analysis using DESeq2 package, GO, and pathway analysis of the differentially expressed transcripts was performed using UniProtKB and KEGG-KAAS server. RESULTS: The results showed that 559 genes differentially expressed between the liver tissue of control mice and CGM treated mice (100 mg/kg b.wt. for 14 days), with adjusted p-value below 0.05, of which 318 genes were significantly upregulated and 241 were downregulated. Further analysis showed that 33 genes which were upregulated (log2FC > 8) in the disease conditions were significantly downregulated, and 32 genes which were downregulated (log2FC < -8) in the disease conditions were significantly upregulated after the treatment with CGM. CONCLUSION: Overall, our study showed CGM has high potential in the prevention and treatment of multiple chronic diseases.

COVID-19, cytokines, inflammation, and spices: How are they related?

BACKGROUND: Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM: To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD: A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS: The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE: As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.

Inflection of Akt/mTOR/STAT-3 cascade in TNF-α induced protein 8 mediated human lung carcinogenesis.

Lung cancer is the leading cause of cancer-related death across the globe. Despite the marked advances in detection and therapeutic approaches, management of lung cancer patients remains a major challenge to oncologists which can be mainly attributed to late stage diagnosis, tumor recurrence and chemoresistance. Therefore, to overthrow these limitations, there arises a vital need to develop effective biomarkers for the successful management of this aggressive cancer type. Notably, TNF-alpha induced protein 8 (TIPE), a nuclear factor-kappa B (NF-κB)-inducible, oncogenic molecule and cytoplasmic protein which is involved in the regulation of T lymphocyte-mediated immunity and different processes in tumor cells such as proliferation, cell death and evasion of growth suppressors, might serve as one such biomarker which would facilitate effective management of lung cancer. Expression studies revealed this protein to be significantly upregulated in different lung cancer types, pathological conditions, stages and grades of lung tumor compared to normal human lung tissues. In addition, knockout of TIPE led to the reduced proliferation, survival, invasion and migration of lung cancer cells. Furthermore, TIPE was found to function through modulation of Akt/mTOR/STAT-3 signaling cascade. This is the first report which shows the involvement of TIPE in tobacco induced lung carcinogenesis. It positively regulated nicotine, NNK, NNN, and BaP induced proliferation, survival and migration of lung cancer cells possibly via Akt/STAT-3 signaling. Thus, this protein possesses important role in the pathogenesis of lung tumor and hence it can be targeted for developing newer therapeutic interventions for the clinico-management of lung cancer.

Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases.

BACKGROUND: Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more. AIM: To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases. METHOD: A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs. KEY FINDINGS: The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties. SIGNIFICANCE: Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.

Cancer drug development: The missing links.

IMPACT STATEMENT: The success rate for cancer drugs which enter into phase 1 clinical trials is utterly less. Why the vast majority of drugs fail is not understood but suggests that pre-clinical studies are not adequate for human diseases. In 1975, as per the Tufts Center for the Study of Drug Development, pharmaceutical industries expended 100 million dollars for research and development of the average FDA approved drug. By 2005, this figure had more than quadrupled, to $1.3 billion. In order to recover their high and risky investment cost, pharmaceutical companies charge more for their products. However, there exists no correlation between drug development cost and actual sale of the drug. This high drug development cost could be due to the reason that all patients might not respond to the drug. Hence, a given drug has to be tested in large number of patients to show drug benefits and obtain significant results.