Enantioselective sensing by collective circular dichroism.

Quantitative determination and in situ monitoring of molecular chirality at extremely low concentrations is still challenging with simple optics because of the molecular-scale mismatch with the incident light wavelength. Advances in spectroscopy1-4 and nanophotonics have successfully lowered the detection limit in enantioselective sensing, as it can bring the microscopic chiral characteristics of molecules into the macroscopic scale5-7 or squeeze the chiral light into the subwavelength scale8-17. Conventional nanophotonic approaches depend mainly on the optical helicity density8,9 by localized resonances within an individual structure, such as localized surface plasmon resonances (LSPRs)10-16 or dielectric Mie resonances17. These approaches use the local chiral hotspots in the immediate vicinity of the structure, whereas the handedness of these hotspots varies spatially. As such, these localized resonance modes tend to be error-prone to the stochasticity of the target molecular orientations, vibrations and local concentrations18,19. Here we identified enantioselective characteristics of collective resonances (CRs)20 arising from assembled 2D crystals of isotropic, 432-symmetric chiral gold nanoparticles (helicoids)21,22. The CRs exhibit a strong and uniform chiral near field over a large volume above the 2D crystal plane, resulting from the collectively spinning, optically induced dipoles at each helicoid. Thus, energy redistribution by molecular back action on the chiral near field shifts the CRs in opposite directions, depending on the handedness of the analyte, maximizing the modulation of the collective circular dichroism (CD).

Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma.

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.

Pivotal role of PD-1/PD-L1 immune checkpoints in immune escape and cancer progression: Their interplay with platelets and FOXP3+Tregs related molecules, clinical implications and combinational potential with phytochemicals.

Immune checkpoint proteins including programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are involved in proliferation, angiogenesis, metastasis, chemoresistance via immune escape and immune tolerance by disturbing cytotoxic T cell activation. Though many clinical trials have been completed in several cancers by using immune checkpoint inhibitors alone or in combination with other agents to date, recently multi-target therapy is considered more attractive than monotherapy, since immune checkpoint proteins work with other components such as surrounding blood vessels, dendritic cells, fibroblasts, macrophages, platelets and extracellular matrix within tumor microenvironment. Thus, in the current review, we look back on research history of immune checkpoint proteins and discuss their associations with platelets or tumor cell induced platelet aggregation (TCIPA) and FOXP3+ regulatory T cells (Tregs) related molecules involved in immune evasion and tumor progression, clinical implications of completed trial results and signaling networks by phytochemicals for combination therapy with immune checkpoint inhibitors and suggest future research perspectives.

Immune functions as a ligand or a receptor, cancer prognosis potential, clinical implication of VISTA in cancer immunotherapy.

Since cancer immunotherapy with immune checkpoint inhibitors of PD/PDL-1 and CTLA-4 limited efficacy to the patients due to resistance during the current decade, novel target is required for customized treatment due to tumor heterogeneity. V-domain Ig-containing suppressor of T cell activation (VISTA), a programmed death protein-1(PD-1) homolog expressed on T cells and on antigen presenting cells(APC), has emerged as a new target in several cancers. Though VISTA inhibitors including CA-170 are considered attractive in cancer immunotherapy to date, the information on VISTA as a potent biomarker of cancer prognosis and its combination therapy is still lacking to date. Thus, in this review, we discussed extracellular domain, ligands, expression, immune functions and clinical implications of VISTA and finally suggested conclusion and perspectives.

Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms.

Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.

Antitumor mechanism of combination of Angelica gigas and Torilis japonica in LNCaP prostate cancer cells via G1 arrest and inhibition of Wnt/ß-catenin and androgen receptor signaling.

The goal of the current study is to assess the antitumor mechanism by the combination (7:3) of Angelica gigas and Torilis japonica (AT) that was found most effective through screening against prostate-specific antigen (PSA) in LNCaP prostate cancer cells. Here, AT reduced the viability and the number of colonies in androgen-dependent LNCaP cells more than in androgen independent PC3 and DU145 cells. Also, AT induced G1 phase arrest, cleaved PARP and caspase 3, activated p27 and decreased the expression of Cyclin D1, Cyclin E, cdk2 in LNCaP cells. Furthermore, AT decreased the expression of PSA and androgen receptor (AR) at mRNA and protein levels in LNCaP cells. Interestingly, AT attenuated the expression of AR, PSA and Wnt-3a and the stability of AR and PSA in LNCaP cells. Furthermore, AT reversed dihydrotestosterone (DHT)-induced upregulation of AR and PSA in LnCaP cells. Notably, AT disrupted the protein-protein interaction, nuclear translocation and fluorescent expression of ß-catenin and AR in LNCaP cells. Consistently, ß-catenin depletion enhanced the decreased expression of AR in AT treated LNCaP cells. Taken together, our findings highlight evidence that AT suppresses the proliferation of LNCaP cells via G1 arrest and inhibition of ß-catenin and AR as a potential anticancer agent.

Moracin D induces apoptosis in prostate cancer cells via activation of PPAR gamma/PKC delta and inhibition of PKC alpha.

Herein, apoptotic mechanism of Moracin D was explored in prostate cancer cells in association with peroxisome proliferator-activated receptor gamma (PPAR-γ)-related signaling involved in lipid metabolism. Moracin D augmented cytotoxicity and sub G1 population in PC3 and DU145 prostate cancer cells, while DU145 cells were more susceptible to Moracin D than PC3 cells. Moracin D attenuated the expression of caspase-3, poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2), and B-cell lymphoma-extra-large (Bcl-xL) in DU145 cells. Consistently, Moracin D significantly augmented the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in DU145 cells. Interestingly, Moracin D activated PPAR-γ and phospho-protein kinase C delta (p-PKC-δ) and inhibited phospho-protein kinase C alpha (p-PKC-α) in DU145 cells. Furthermore, STRING bioinformatic analysis reveals that PPAR-γ interacts with nuclear factor-κB (NF-κB) that binds to PKC-α/PKC-δ or protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). Indeed, Moracin D decreased phosphorylation of NF-κB, ERK, and AKT in DU145 cells. Conversely, PPAR-γ inhibitor GW9662 reduced the apoptotic ability of Moracin D to activate caspase 3 and PARP in DU145 cells. Taken together, these findings provide a novel insight that activation of PPAR-γ/p-PKC-δ and inhibition of p-PKC-α are critically involved in Moracin D-induced apoptosis in DU145 prostate cancer cells.

Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c-Myc signaling.

Since the AKT/mammalian target of rapamycin (mTOR)/c-Myc signaling plays a pivotal role in the modulation of aerobic glycolysis and tumor growth, in the present study, the role of AKT/mTOR/c-Myc signaling in the apoptotic effect of Compound K (CK), an active ginseng saponin metabolite, was explored in HepG2 and Huh7 human hepatocellular carcinoma cells (HCCs). Here, CK exerted significant cytotoxicity, increased sub-G1, and attenuated the expression of pro-Poly (ADP-ribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HepG2 and Huh7 cells. Consistently, CK suppressed AKT/mTOR/c-Myc and their downstreams such as Hexokinase 2 (HK2) and pyruvate kinase isozymes M2 (PKM2) in HepG2 and Huh7 cells. Additionally, CK reduced c-Myc stability in the presence or absence of cycloheximide in HepG2 cells. Furthermore, AKT inhibitor LY294002 blocked the expression of p-AKT, c-Myc, HK2, PKM2, and pro-cas3 in HepG2 cells. Pyruvate blocked the ability of CK to inhibit p-AKT, p-mTOR, HK2, and pro-Cas3 in treated HepG2 cells. Overall, these findings provide evidence that CK induces apoptosis via inhibition of glycolysis and AKT/mTOR/c-Myc signaling in HCC cells as a potent anticancer candidate for liver cancer clinical translation.

Ribosomal protein L5 mediated inhibition of c-Myc is critically involved in sanggenon G induced apoptosis in non-small lung cancer cells.

Though Sanggenon G (SanG) from root bark of Morus alba was known to exhibit anti-oxidant and anti-depressant effects, its underlying mechanisms still remain unclear. Herein SanG reduced the viability of A549 and H1299 non-small lung cancer cells (NSCLCs). Also, SanG increased sub-G1 population via inhibition of cyclin D1, cyclin E, CDK2, CDK4 and Bcl-2, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 in A549 and H1299 cells. Of note, SanG effectively inhibited c-Myc expression by activating ribosomal protein L5 (RPL5) and reducing c-Myc stability even in the presence of cycloheximide and 20% serum in A549 cells. Furthermore, SanG enhanced the apoptotic effect with doxorubicin in A549 cells. Taken together, our results for the first time provide novel evidence that SanG suppresses proliferation and induces apoptosis via caspase-3 activation and RPL5 mediated inhibition of c-Myc with combinational potential with doxorubicin.

MicroRNA216b mediated downregulation of HSP27/STAT3/AKT signaling is critically involved in lambertianic acid induced apoptosis in human cervical cancers.

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers.

Suppression of phosphoinositide 3-kinase/phosphoinositide-dependent kinase-1/serum and glucocorticoid-induced protein kinase pathway.

In the current study, the pivotal roles of serum and glucocorticoid-induced protein kinase (SGK1) and NF-kB related signalings known as prognostic biomarkers in cervical cancers were explored in the antitumor effect of a ginseng saponin metabolite compound K (CK) in HeLa and SiHa cervical cancer cells. CK exerted significant cytotoxicity, induced sub-G1 accumulation, and attenuated the expression of proPoly (ADP-ribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HeLa cells more than in SiHa cells. CK inhibited phosphorylation of SGK1 and its upstream genes, phosphoinositide 3-kinases (PI3K), and phosphoinositide-dependent kinase-1 (PDK1) in HeLa cells. In addition, CK suppressed the phosphorylation of SGK1, NF-κB, and inhibitor of kappa B (IκB) and also NF-κB target genes such as X-linked inhibitor of apoptosis protein and B-cell lymphoma 2 (Bcl-2) in HeLa cells. Notably, Immunoprecipitation revealed that SGK1 binds to PI3K or PDK1 and also CK disturbed the binding between SGK1 and PI3K or PDK1 in HeLa cells. Furthermore, PI3K inhibitor LY294002 decreased expression of PI3K, p-PDK1, p-SGK1, and pro-caspase3 and SGK1 inhibitor GSK650394 also reduced expression of NF-κB and pro-caspase3 just like CK in HeLa cells. Overall, these findings suggest that CK induces apoptosis via suppression of PI3K/PDK1/SGK1 and NF-κB signaling axis.

Apoptotic and antihepatofibrotic effect of honokiol via activation of GSK3ß and suppression of Wnt/ß-catenin pathway in hepatic stellate cells.

Though honokiol, derived from the Magnolia tree, was known to suppress renal fibrosis, pulmonary fibrosis, non-alcoholic steatoheptitis, inflammation and cancers, the underlying antifibrotic mechanisms of honokiol are not fully understood in hepatic stellate cells until now. Thus, in the present study, inhibitory mechanism of honokiol on liver fibrosis was elucidated mainly in hepatic stellate cells (HSCs) by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and western-blotting. Honokiol exerted cytotoxicity in LX-2, HSC-T6 and Hep-G2 cells. Honokiol increased sub G1 population and activated caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) in HSCs. Moreover, honokiol attenuated the expression of alpha smooth muscle actin (α-SMA), transforming growth factor beta 1 (TGF-ß1), phospho-Smad3, phospho-AKT, cyclin D1, c-Myc, Wnt3a, ß-catenin, and activated phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) in HSCs. Conversely, GSK3ß inhibitor SB216763 reversed the effect of honokiol on PARP, α-SMA, phospho-GSK3ß, ß-catenin and sub G1 population in LX-2 cells. Overall, honokiol exerts apoptotic and antifibrotic effects via activation of GSK3ß and inhibition of Wnt3a/ß-catenin signalling pathway.

Inhibition of TMPRSS4 mediated epithelial-mesenchymal transition is critically involved in antimetastatic effect of melatonin in colorectal cancers.

In the current study, the underlying anti-metastatic mechanism of melatonin contained in some edible plants was explored in association with transmembrane protease serine 4 (TMPRSS4) mediated metastasis and epithelial-mesenchymal transition (EMT) signaling in human HCT15 and SW620 colorectal cancer cells. Here, TMPRSS4 was highly expressed in HCT15, but was weakly expressed in SW620 cells. Melatonin exerted weak cytotoxicity, decreased invasion, adhesion, and migration, and attenuated the expression of TMPRSS4, cyclin E, pro-urokinase-type plasminogen activator (pro-uPA), p-signal transducer and activator of transcription 3 (p-STAT3), p-focal adhesion kinase (p-FAK), Snail and increased the expression of E-cadherin, p27, pp38 and p-Jun N-terminal kinases (p-JNK) in HCT15 cells. Conversely, overexpression of TMPRSS4 reduced the ability of melatonin to activate E-cadherin and reduce Snail. Furthermore, even in SW620 cells transfected with TMPRSS4-overexpression plasmid, melatonin effectively suppressed invasion and migration along with decreased expression of Snail, cyclin A, cyclin E, pro-uPA and p-FAK and increased expression of E-cadherin and p27. Overall, these findings provide evidence that melatonin suppresses metastasis in colon cancer cells via inhibition of TMPRSS4 mediated EMT.

Antitumor Effect of Morusin via G1 Arrest and Antiglycolysis by AMPK Activation in Hepatocellular Cancer.

Though Morusin isolated from the root of Morus alba was known to have antioxidant, anti-inflammatory, antiangiogenic, antimigratory, and apoptotic effects, the underlying antitumor effect of Morusin is not fully understood on the glycolysis of liver cancers. Hence, in the current study, the antitumor mechanism of Morusin was explored in Hep3B and Huh7 hepatocellular carcninomas (HCC) in association with glycolysis and G1 arrest. Herein, Morusin significantly reduced the viability and the number of colonies in Hep3B and Huh7 cells. Moreover, Morusin significantly increased G1 arrest, attenuated the expression of cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) and upregulated p21 and p27 in Hep3B and Huh7 cells. Interestingly, Morusin significantly activated phosphorylation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but attenuated the expression of the p-mammalian target of protein kinase B (AKT), rapamycin (mTOR), c-Myc, hexokinase 2(HK2), pyruvate kinases type M2 (PKM2), and lactate dehydrogenase (LDH) in Hep3B and Huh7 cells. Consistently, Morusin suppressed lactate, glucose, and adenosine triphosphate (ATP) in Hep3B and Huh7 cells. Conversely, the AMPK inhibitor compound C reduced the ability of Morusin to activate AMPK and attenuate the expression of p-mTOR, HK2, PKM2, and LDH-A and suppressed G1 arrest induced by Morusin in Hep3B cells. Overall, these findings suggest that Morusin exerts an antitumor effect in HCCs via AMPK mediated G1 arrest and antiglycolysis as a potent dietary anticancer candidate.

Recent Advances in Nanotechnology with Nano-Phytochemicals: Molecular Mechanisms and Clinical Implications in Cancer Progression.

Biocompatible nanoparticles (NPs) containing polymers, lipids (liposomes and micelles), dendrimers, ferritin, carbon nanotubes, quantum dots, ceramic, magnetic materials, and gold/silver have contributed to imaging diagnosis and targeted cancer therapy. However, only some NP drugs, including Doxil® (liposome-encapsulated doxorubicin), Abraxane® (albumin-bound paclitaxel), and Oncaspar® (PEG-Asparaginase), have emerged on the pharmaceutical market to date. By contrast, several phytochemicals that were found to be effective in cultured cancer cells and animal studies have not shown significant efficacy in humans due to poor bioavailability and absorption, rapid clearance, resistance, and toxicity. Research to overcome these drawbacks by using phytochemical NPs remains in the early stages of clinical translation. Thus, in the current review, we discuss the progress in nanotechnology, research milestones, the molecular mechanisms of phytochemicals encapsulated in NPs, and clinical implications. Several challenges that must be overcome and future research perspectives are also described.

Colloidal Photonic Assemblies for Colorful Radiative Cooling.

Radiative cooling has proven to be a powerful strategy for sustainable thermal management. Nanophotonic structures enabling broadband reflection lead to minimization of sunlight absorption, which has brought nighttime-limited radiative cooling into daytime applications. However, this broadband reflection strategy in turn restricts the accessible colorization of radiative coolers to white or neutral, consequently hindering their practical applications, particularly for aesthetic purposes. With a few exceptions, selective absorption at a specific visible wavelength has been the most prevalent paradigm for colorization of radiative coolers. However, this absorption-based colorization inevitably makes the radiative cooler prone to heating, thus decreasing the cooling efficiency. Here, we demonstrate an undiscovered usage of opals for advancing color-preserved daytime radiative coolers. Opals, which have served mainly as Bragg reflective color pigments thus far, can be considered an effective homogeneous medium in the mid-infrared region. Thus, opals can also be envisioned as reflectively colorful metamaterials capable of radiative cooling even under the direct summer sun. Together with the soft fluidity of colloidal suspensions, opals can serve as platforms for easy-to-craft, large-scale, and colorful radiative coolers with minimal solar absorption.

Antitumor Effect of Pyrogallol via miR-134 Mediated S Phase Arrest and Inhibition of PI3K/AKT/Skp2/cMyc Signaling in Hepatocellular Carcinoma.

Though Pyrogallol, one of the natural polyphenols, was known to have anti-inflammatory and antitumor effects in breast and colon cancers, the underlying antitumor mechanisms of Pyrogallol, still remain unclear so far. Here, the antitumor mechanisms of Pyrogallol were elucidated in Hep3B and Huh7 hepatocellular carcinoma cells (HCCs). Pyrogallol showed significant cytotoxicity and reduced the number of colonies in Hep3B and Huh7 cells. Interestingly, Pyrogallol induced S-phase arrest and attenuated the protein expression of CyclinD1, Cyclin E, Cyclin A, c-Myc, S-phase kinase-associated protein 2 (Skp2), p-AKT, PI3K, increased the protein expression of p27, and also reduced the fluorescent expression of Cyclin E in Hep3B and Huh7 cells. Furthermore, Pyrogallol disturbed the interaction between Skp2, p27, and c-Myc in Huh7 cells. Notably, Pyrogallol upregulated miRNA levels of miR-134, and conversely, miR-134 inhibition rescued the decreased expression levels of c-Myc, Cyclin E, and Cyclin D1 and increased the expression of p27 by Pyrogallol in Huh7 cells. Taken together, our findings provide insight that Pyrogallol exerts antitumor effects in HCCs via miR-134 activation-mediated S-phase arrest and inhibition of PI3K/AKT/Skp2/cMyc signaling as a potent anticancer candidate.

Suppression of STAT3 Phosphorylation and RelA/p65 Acetylation Mediated by MicroRNA134 Plays a Pivotal Role in the Apoptotic Effect of Lambertianic Acid.

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.

Farnesiferol C Induces Apoptosis in Chronic Myelogenous Leukemia Cells as an Imatinib Sensitizer via Caspase Activation and HDAC (Histone Deacetylase) Inactivation.

Herein the underlying apoptotic mechanism of Farnesiferol C (FC) derived from Ferula assafoetida was elucidated in chronic myelogenous leukemia (CML) K562 and KBM5 cells. FC showed significant cytotoxicity in K562 and KBM5 cells, more so than in U937 and UL-60 acute myeloid leukemia (AML) cells. Cleaved PARP and caspase 9/3 attenuated the expression of Bcl2 and induced G1 arrest in K562 and KBM5 cells. Also, FC effectively abrogated the expression of cell cycle related proteins, such as: Cyclin D1, Cyclin E, Cyclin B1 in K562, and KBM5 cells, but caspase 3 inhibitor Z-DEVD-FMK rescued the cleavages of caspase 3 and PARP induced by FC in K562 cells. Of note, FC decreased histone deacetylase 1 (HDAC1) and HDAC2, and enhanced histone H3 acetylation K18 (Ac-H3K18) in K562 and KBM5 cells. Furthermore, combination of FC and Imatinib enhanced the apoptotic effect of Imatinib as a potent Imatinib sensitizer in K562 cells. Overall, our findings provide scientific evidence that inactivation of HDAC and caspase activation mediate FC induced apoptosis in CML cells.

Plumbagin reduces osteopontin-induced invasion through inhibiting the Rho-associated kinase signaling pathway in A549 cells and suppresses osteopontin-induced lung metastasis in BalB/c mice.

Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths in both men and women in the United States. It has been recently demonstrated that osteopontin (OPN) effectively inhibits cofilin activity through the focal adhesion kinase (FAK)/AKT/Rho-associated kinase (ROCK) pathway to induce the invasion of human non-small cell lung cancer (NSCLC) cells. Plumbagin was isolated from the roots of the medicinal plant Plumbago zeylanica L. and has been reported to possess anticancer activities. However, the molecular mechanisms by which plumbagin inhibits the invasion of cancer cells is still unclear. In this study, the anti-invasive and anti-metastatic mechanisms of plumbagin were investigated in OPN-treated NSCLC A549 cells. OPN effectively induced the motility and invasion of NSCLC A549 cells and H1299 cells, which was strongly suppressed by plumbagin with no evidence of cytotoxicity. In addition, lamellipodia formation at the leading edge of cells by OPN was dramatically decreased in plumbagin-treated cells. Plumbagin caused an effective inhibition in OPN-induced the expression of ROCK1 as well as the phosphorylation of LIM kinase 1 and 2 (LIMK1/2), and cofilin. OPN-induced the phosphorylation of FAK and AKT was impaired without affecting their total forms by plumbagin treatment. OPN facilitated metastatic lung colonization, which was effectively suppressed in plumbagin-treated mice. Taken together, these results suggest that plumbagin reduces OPN-induced the invasion of NSCLC A549 cells, which resulted from inhibiting the ROCK pathway mediated by the FAK/AKT pathway and suppresses lung metastasis in vivo.