Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.

Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasis in vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3-mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.

Complexity of Tumor Microenvironment: Therapeutic Role of Curcumin and Its Metabolites.

The tumor microenvironment (TME) is a complex network of cellular and non-cellular components surrounding the tumor. The cellular component includes fibroblasts, adipocytes, endothelial cells, and immune cells, while non-cellular components are tumor vasculature, extracellular matrix and signaling molecules. The tumor cells have constant close interaction with their surrounding TME components that facilitate their growth, survival, and metastasis. Targeting a complex TME network and its interaction with the tumor can offer a novel strategy to disrupt cancer cell progression. Curcumin, from turmeric rhizome, is recognized as a safe and effective natural therapeutic agent against multiple diseases including cancer. Here the effects of curcumin and its metabolites on tumor-TME interaction modulating ability have been described. Curcumin and its metabolites regulate TME by inhibiting the growth of its cellular components such as cancer-associated adipocytes, cancer-associated fibroblast, tumor endothelial cells, tumor-stimulating immune cells, and inducing anticancer immune cells. They also inhibit the interplay of tumor cells to TME by suppressing non-cellular components such as extracellular matrix, and associated tumor promoting signaling-pathways. In addition, curcumin inhibits the inflammatory environment, suppresses angiogenic factors, and increases antioxidant status in TME. Overall, curcumin has the capability to regulate TME components and their interaction with tumor cells.

Drug rechanneling: A novel paradigm for cancer treatment.

Cancer continues to be one of the leading contributors towards global disease burden. According to NIH, cancer incidence rate per year will increase to 23.6 million by 2030. Even though cancer continues to be a major proportion of the disease burden worldwide, it has the lowest clinical trial success rate amongst other diseases. Hence, there is an unmet need for novel, affordable and effective anti-neoplastic medications. As a result, a growing interest has sparkled amongst researchers towards drug repurposing. Drug repurposing follows the principle of polypharmacology, which states, "any drug with multiple targets or off targets can present several modes of action". Drug repurposing also known as drug rechanneling, or drug repositioning is an economic and reliable approach that identifies new disease treatment of already approved drugs. Repurposing guarantees expedited access of drugs to the patients as these drugs are already FDA approved and their safety and toxicity profile is completely established. Epidemiological studies have identified the decreased occurrence of oncological or non-oncological conditions in patients undergoing treatment with FDA approved drugs. Data from multiple experimental studies and clinical observations have depicted that several non-neoplastic drugs have potential anticancer activity. In this review, we have summarized the potential anti-cancer effects of anti-psychotic, anti-malarial, anti-viral and anti-emetic drugs with a brief overview on their mechanism and pathways in different cancer types. This review highlights promising evidences for the repurposing of drugs in oncology.

Metal-Curcumin Complexes in Therapeutics: An Approach to Enhance Pharmacological Effects of Curcumin.

Curcumin, an active component of the rhizome turmeric, has gained much attention as a plant-based compound with pleiotropic pharmacological properties. It possesses anti-inflammatory, antioxidant, hypoglycemic, antimicrobial, neuroprotective, and immunomodulatory activities. However, the health-promoting utility of curcumin is constrained due to its hydrophobic nature, water insolubility, poor bioavailability, rapid metabolism, and systemic elimination. Therefore, an innovative stride was taken, and complexes of metals with curcumin have been synthesized. Curcumin usually reacts with metals through the ß-diketone moiety to generate metal-curcumin complexes. It is well established that curcumin strongly chelates several metal ions, including boron, cobalt, copper, gallium, gadolinium, gold, lanthanum, manganese, nickel, iron, palladium, platinum, ruthenium, silver, vanadium, and zinc. In this review, the pharmacological, chemopreventive, and therapeutic activities of metal-curcumin complexes are discussed. Metal-curcumin complexes increase the solubility, cellular uptake, and bioavailability and improve the antioxidant, anti-inflammatory, antimicrobial, and antiviral effects of curcumin. Metal-curcumin complexes have also demonstrated efficacy against various chronic diseases, including cancer, arthritis, osteoporosis, and neurological disorders such as Alzheimer's disease. These biological activities of metal-curcumin complexes were associated with the modulation of inflammatory mediators, transcription factors, protein kinases, antiapoptotic proteins, lipid peroxidation, and antioxidant enzymes. In addition, metal-curcumin complexes have shown usefulness in biological imaging and radioimaging. The future use of metal-curcumin complexes may represent a new approach in the prevention and treatment of chronic diseases.

Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions.

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

Targeting Glioblastoma Tumor Microenvironment.

Glioblastoma, also referred to as glioblastoma multiforme (GBM), is an aggressive type of brain cancer. The prognosis for GBM is poor with an average medium survival rate of 12-15 months. GBM is highly challenging to treat due to neural stem cells phenotypic variations. These variations are determined by the tumor microenvironment (TME), which refers to all the molecules, cells, and structures that encompass and support other cells and tissues. Along with these, other vital components of the TME are fibroblasts, immune and inflammatory cells, blood and lymphatic vascular networks, extracellular matrix, and signaling molecules. This chapter provides an in-depth review of the vital components that form the TME and methods currently under development attempting to target each key area.

Free Radicals as a Double-Edged Sword: The Cancer Preventive and Therapeutic Roles of Curcumin.

Free radicals, generally composed of reactive oxygen species (ROS) and reactive nitrogen species (RNS), are generated in the body by various endogenous and exogenous systems. The overproduction of free radicals is known to cause several chronic diseases including cancer. However, increased production of free radicals by chemotherapeutic drugs is also associated with apoptosis in cancer cells, indicating the dual nature of free radicals. Among various natural compounds, curcumin manifests as an antioxidant in normal cells that helps in the prevention of carcinogenesis. It also acts as a prooxidant in cancer cells and is associated with inducing apoptosis. Curcumin quenches free radicals, induces antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and upregulates antioxidative protein markers-Nrf2 and HO-1 that lead to the suppression of cellular oxidative stress. In cancer cells, curcumin aggressively increases ROS that results in DNA damage and subsequently cancer cell death. It also sensitizes drug-resistant cancer cells and increases the anticancer effects of chemotherapeutic drugs. Thus, curcumin shows beneficial effects in prevention, treatment and chemosensitization of cancer cells. In this review, we will discuss the dual role of free radicals as well as the chemopreventive and chemotherapeutic effects of curcumin and its analogues against cancer.

Role of Phytochemicals in Cancer Prevention.

The use of synthetic, natural, or biological agents to minimize the occurrence of cancer in healthy individuals is defined as cancer chemoprevention. Chemopreventive agents inhibit the development of cancer either by impeding DNA damage, which leads to malignancy or by reversing or blocking the division of premalignant cells with DNA damage. The benefit of this approach has been demonstrated in clinical trials of breast, prostate, and colon cancer. The continuous increase in cancer cases, failure of conventional chemotherapies to control cancer, and excessive toxicity of chemotherapies clearly demand an alternative approach. The first trial to show benefit of chemoprevention was undertaken in breast cancer patients with the use of tamoxifen, which demonstrated a significant decrease in invasive breast cancer. The success of using chemopreventive agents for protecting the high risk populations from cancer indicates that the strategy is rational and promising. Dietary components such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopenes, benzyl isothiocyanate, phenethyl isothiocyanate, and piperlongumine have demonstrated inhibitory effects on cancer cells indicating that they may serve as chemopreventive agents. In this review, we have addressed the mechanism of chemopreventive and anticancer effects of several natural agents.

Chronic diseases, inflammation, and spices: how are they linked?

Extensive research within the last several decades has revealed that the major risk factors for most chronic diseases are infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and diet. It is now well established that these factors induce chronic diseases through induction of inflammation. However, inflammation could be either acute or chronic. Acute inflammation persists for a short duration and is the host defense against infections and allergens, whereas the chronic inflammation persists for a long time and leads to many chronic diseases including cancer, cardiovascular diseases, neurodegenerative diseases, respiratory diseases, etc. Numerous lines of evidence suggest that the aforementioned risk factors induced cancer through chronic inflammation. First, transcription factors NF-κB and STAT3 that regulate expression of inflammatory gene products, have been found to be constitutively active in most cancers; second, chronic inflammation such as pancreatitis, prostatitis, hepatitis etc. leads to cancers; third, activation of NF-κB and STAT3 leads to cancer cell proliferation, survival, invasion, angiogenesis and metastasis; fourth, activation of NF-κB and STAT3 leads to resistance to chemotherapy and radiation, and hypoxia and acidic conditions activate these transcription factors. Therefore, targeting these pathways may provide opportunities for both prevention and treatment of cancer and other chronic diseases. We will discuss in this review the potential of various dietary agents such as spices and its components in the suppression of inflammatory pathways and their roles in the prevention and therapy of cancer and other chronic diseases. In fact, epidemiological studies do indicate that cancer incidence in countries such as India where spices are consumed daily is much lower (94/100,000) than those where spices are not consumed such as United States (318/100,000), suggesting the potential role of spices in cancer prevention.

γ-Tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by down-regulating multiple molecules.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide and even develops resistance to chemotherapeutic agents over time. As a result survival for patients with CRC remains poor. METHOD: We investigated both in vitro and in vivo effects of γ-tocotrienol (γ-T3) alone and in combination with capecitabine. Apoptosis and cytotoxicity assays were performed by MTT and FACS analysis, whereas expression of proteins was investigated using western blotting and immunohistochemistry. RESULTS: The γ-T3 inhibited the proliferation of CRC cells with wild-type or mutated KRAS. It also induced apoptosis, inhibited colony formation, and suppressed key regulators of cell survival, cell proliferation, invasion, angiogenesis, and metastasis. Furthermore, γ-T3 enhanced the anticancer effects of capecitabine in CRC cells. In a nude mouse xenograft model of human CRC, oral administration of γ-T3 inhibited tumour growth and enhanced the antitumour efficacy of capecitabine. Western blot and immunohistochemical analysis results indicated that expression of Ki-67, cyclin D1, MMP-9, CXCR4, NF-κB/p65, and VEGF was lower in tumour tissue from the combination treatment group. Combination treatment also downregulated NF-κB and NF-κB-regulated gene products. CONCLUSIONS: Our findings suggest that γ-T3 inhibited the growth of human CRC and sensitised CRC to capecitabine by regulating proteins linked to tumourigenesis.

Calebin A downregulates osteoclastogenesis through suppression of RANKL signalling.

Osteoporosis is a bone disease that is exacerbated by aging and age-associated chronic diseases such as cancer. Cancer-induced bone loss is usually treated with bisphosphonates or denosumab, an antibody against receptor activator of nuclear factor (NF)-κB ligand (RANKL). Because these drugs are expensive and have numerous side effects and high rates of toxicity, safer, more effective, and more affordable therapies for osteoporosis are still needed. We identified a compound, calebin A (CA), derived from turmeric (Curcuma longa) that affects osteoclastogenesis through modulation of the RANKL signalling pathway. The CA's effect on NF-κB activation was examined by electrophoretic mobility shift assay. Using mouse macrophages in vitro model, we found that CA suppressed RANKL-induced osteoclast differentiation of macrophages into osteoclasts, and downregulate RANKL-induced osteoclastogenesis-related marker gene expression, including NFATc-1, TRAP, CTR, and cathepsin K. CA also suppressed the osteoclastogenesis induced by multiple myeloma and breast cancer cells. This effect of CA was correlated with suppression of the phosphorylation and degradation of inhibitor of κB and, thus, inhibition of NF-κB activation. Furthermore, we found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, demonstrating that the NF-κB signalling pathway is mandatory for RANKL-induced osteoclastogenesis. Our results conclusively indicate that CA downmodulates the osteoclastogenesis induced by RANKL and by tumour cells through suppression of NF-κB pathway.

Identification of a novel compound (ß-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: comparison with curcumin.

Considering that as many as 80% of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, ß-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, α-curcumene, ar-turmerone, α-turmerone, ß-turmerone, and γ-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-κB-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin.

Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols.

Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases.

Curcumin glucuronides: assessing the proliferative activity against human cell lines.

A gram scale synthesis of the glucuronide metabolites of curcumin were completed in four steps. The newly synthesized curcumin glucuronide compounds 2 and 3 along with curcumin 1 were tested and their anti-proliferative effects against KBM-5, Jurkat cell, U266, and A549 cell lines were reported. Biological data revealed that as much as 1 µM curcumin 1 exhibited anticancer activity and almost 100% cell kill was noted at 10 µM on two out of four cell lines; while curcumin mono-glucuronide 2 as well as di-glucuronide 3 displayed no suppression of cell proliferation.

Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses.

Curcumin (diferuloylmethane), a golden pigment from turmeric, has been linked with antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antidiabetic properties. Most of the these activities have been assigned to methoxy, hydroxyl, α,ß-unsaturated carbonyl moiety or to diketone groups present in curcumin. One of the major metabolites of curcumin is tetrahydrocurcumin (THC), which lacks α,ß-unsaturated carbonyl moiety and is white in color. Whether THC is superior to curcumin on a molecular level is unclear and thus is the focus of this review. Various studies suggest that curcumin is a more potent antioxidant than THC; curcumin (but not THC) can bind and inhibit numerous targets including DNA (cytosine-5)-methyltransferase-1, heme oxygenase-1, Nrf2, ß-catenin, cyclooxygenase-2, NF-kappaB, inducible nitric oxide synthase, nitric oxide, amyloid plaques, reactive oxygen species, vascular endothelial growth factor, cyclin D1, glutathione, P300/CBP, 5-lipoxygenase, cytosolic phospholipase A2, prostaglandin E2, inhibitor of NF-kappaB kinase-1, -2, P38MAPK, p-Tau, tumor necrosis factor-α, forkhead box O3a, CRAC; curcumin can inhibit tumor cell growth and suppress cellular entry of viruses such as influenza A virus and hepatitis C virus much more effectively than THC; curcumin affects membrane mobility; and curcumin is also more effective than THC in suppressing phorbol-ester-induced tumor promotion. Other studies, however, suggest that THC is superior to curcumin for induction of GSH peroxidase, glutathione-S-transferase, NADPH: quinone reductase, and quenching of free radicals. Most studies have indicated that THC exhibits higher antioxidant activity, but curcumin exhibits both pro-oxidant and antioxidant properties.

Colorectal carcinoma cell targeting aromatherapy with Teucrium ramosissimum essential oil to sensitize TRAIL/Apo2L-induced HCT-116 cell death.

This report drives insights for the investigation of the underlying mechanisms of antitumor effects of Teucrium ramosissimum (TrS) essential oil (EO) that elicits colon tumor protection via activation of cell death machinery. A study of the aerial part phytocomplex was performed by FTIR spectra and GC/MS. In vivo colon carcinogenesis induced by LPS was carried out using mouse model. HCT-116 cells were coincubated with TrS EO and TRAIL-resistant cancer cells, and then cell lysates were assessed using Western blotting technique for death and decoy receptor expression. TrS essential oil potentiates TRAIL-mediated apoptosis cell death of HCT-116 as detected by PARP cleavage and caspase activation. Further data suggest that TrS up-regulates DR 5/4 expression, and down-regulates DcRs expression. Additionally, TrS potentiates apoptosis in TRAIL-resistant tumor cells through induction of MAPK signalling components, including ERK, p38 kinase, JNK, and activation of CHOP, and SP1, involved in DR5 expression. Moreover, Teucrium EO phytoconstituents mediate HCT-116 cells apoptosis by evoking cell cycle arrest at the G1 and G2/M phase through diminishing the expression of cyclin D1 acting as a potent multitargeted factors of inhibition of JAK/STAT oncogenic signaling pathway. These results demonstrate that TRAIL-induced apoptosis enhancing effect of TrS mediated through proto-oncogene expression in HCT-116. TrS administered intragastrically is able to prevent tumor of colon by stopping carcinogenesis process and impede tumor cell growth in in vivo analysis promoted by LPS. On the whole, our results revealed that TrS is an effective antitcancer agent through the induction of transcription factor and kinases, either are needed to trigger Apo2L receptors.

3-Formylchromone interacts with cysteine 38 in p65 protein and with cysteine 179 in IκBα kinase, leading to down-regulation of nuclear factor-κB (NF-κB)-regulated gene products and sensitization of tumor cells.

3-Formylchromone (3-FC) has been associated with anticancer potential through a mechanism yet to be elucidated. Because of the critical role of NF-κB in tumorigenesis, we investigated the effect of this agent on the NF-κB activation pathway. Whether activated by inflammatory agents (such as TNF-α and endotoxin) or tumor promoters (such as phorbol ester and okadaic acid), 3-FC suppressed NF-κB activation. It also inhibited constitutive NF-κB expressed by most tumor cells. This activity correlated with sequential inhibition of IκBα kinase (IKK) activation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and reporter gene expression. We found that 3-FC inhibited the direct binding of p65 to DNA, and this binding was reversed by a reducing agent, thus suggesting a role for the cysteine residue. Furthermore, mutation of Cys38 to Ser in p65 abolished this effect of the chromone. This result was confirmed by a docking study. 3-FC also inhibited IKK activation directly, and the reducing agent reversed this inhibition. Furthermore, mutation of Cys179 to Ala in IKK abolished the effect of the chromone. Suppression of NF-κB activation led to inhibition of anti-apoptotic (Bcl-2, Bcl-xL, survivin, and cIAP-1), proliferative (cyclin D1 and COX-2), invasive (MMP-9 and ICAM-1), and angiogenic (VEGF) gene products and sensitization of tumor cells to cytokines. Thus, this study shows that modification of cysteine residues in IKK and p65 by 3-FC leads to inhibition of the NF-κB activation pathway, suppression of anti-apoptotic gene products, and potentiation of apoptosis in tumor cells.