Substantial Anticancer Activity Research Articles

A Marine-Derived Small Molecule Inhibits Prostate Cancer Growth by Promoting Endoplasmic Reticulum Stress Induced Apoptosis and Autophagy.

MHO7 (6-epi-ophiobolin G), a novel component extracted from a mangrove fungus, exhibits significant anticancer effects against breast cancer. However, the precise mechanism underlying the anticancer effects of MHO7 in prostate cancer (PCa) is yet to be fully elucidated. Therefore, this study was undertaken to assess the effect of MHO7 on PCa cells and elucidate its underlying mechanism. A series of in vitro experiments were conducted, including Cell Counting Kit-8, and plate clone formation assays, flow cytometry analysis, electron microscopy, immunofluorescence staining, western blotting, and molecular dynamics simulation. Additionally, in vivo tumor xenograft models were employed. Our findings revealed that MHO7 could induce cellular autophagy at low concentration (2 μM) and apoptosis at relatively high concentration (4 and 8 μM), leading to significant PCa cell growth inhibition. Furthermore, MHO7 triggered endoplasmic reticulum (ER) stress, which subsequently stimulated autophagy and apoptosis via IRE1α/XBP-1s signaling pathway activation. Notably, IRE1α knockdown markedly reduced MHO7-induced autophagy and apoptosis. Moreover, MHO7 targeted the IRE1α protein, thereby enhancing its stability. MHO7 also exhibited substantial anticancer activity in tumor xenograft models. Our study revealed that MHO7 holds considerable potential as an anticancer agent against PCa, attributable to its activation of ER stress-induced autophagy and apoptosis at different concentrations, facilitated by the upregulation of IRE1α expression.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer

BackgroundElevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.MethodsWe developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.ResultsModel simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects.ConclusionsThis work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

New Imidazo[4,5‐c]pyridine‐piperidine Hybrids as Potential Anti‐cancer Agents and In‐Silico Studies

AbstractDesign and synthesis of a series of novel hybrid molecules that combine Imidazo[4,5‐c] pyridines with piperdines are presented in this paper. Total 17 derivatives were meticulously synthesized and characterized using 1H NMR, 13C NMR, MS and elemental analysis techniques. The in vitroanticancer activities are estimated by verifying their effectiveness against the MCF‐7 human breast adenocarcinoma and A549 lung cancer cell line, with cisplatin and doxorubicin serving as reference drugs. Several of these compounds demonstrated significant potential, displaying IC50 values within the range of 12.26–84.5 μM for A549, and 13.37–69.82 μM for MCF‐7. Notably, compound 11 bis found to be more potent than the standard drug cisplatin with an IC50 of 12.26±0.8 μM against A549 cells, while compound 11 d exhibited highest inhibition with an IC50 of 13.37±0.4 μM against MCF‐7 cells. Although its effectiveness was moderately lower when compared to doxorubicin, it still retained substantial anticancer activity. Molecular docking studies were performed to decouple the binding affinity and ligand interactions of the compounds with the estrogen receptor alpha (ERα) (PDB ID: 3ERT). The pharmacokinetic evaluation revealed favourable drug‐likeness properties for all the molecules, suggesting their potential as therapeutic agents.

Sustainable Gold Nanoparticle (Au-NP) Growth within Interspaces of Porphyrinic Zirconium-Based Metal-Organic Frameworks: Green Synthesis of PCN-224/Au-NPs and Its Anticancer Effect on Colorectal Cancer Cells Assay.

In this work, a simple green synthesis method of the novel metal-organic framework (MOF) nanocomposite PCN-224/Au-NPs (Au-NPs = gold nanoparticles) is described. In this regard, initially, PCN-224 was synthesized. Afterward, in a single-step, one-pot procedure, under visible-light irradiation, Au-NPs were fabricated on PCN-224. The cytotoxicity effect of the synthesized PCN-224/Au-NPs nanocomposite was investigated in human colon cancer cells. Determination of the apoptosis induction was done by the Annexin- V/propidium iodide flow cytometry method. Besides, to ascertain the biocompatibility of the synthesized sample, the cytotoxicity of PCN-224/Au-NPs was evaluated on the human embryonic kidney (HEK)-293 cell line. The substantial anticancer activity with the biocompatibility of the structure, the green facile synthesis, and the MOF surface of the synthesized nanocomposite make it special for utilization in therapeutic applications.

Multifunctional role of engineered tin oxide nanoparticles with the variation of calcination temperatures

In the present work, we have investigated the effect of calcination temperature on the structural, morphological, optical, and electrical properties of synthesized tin oxide NPs using various spectroscopic techniques. The decrease in the crystallite size and the change in the phase transformation from SnO litharge to SnO2 rutile structure have been noticed as a function of calcination temperature. The synthesized NPs are optically active, exhibit broad absorption and narrow emission peaks and have shown the behavior of the quantum confinement effect. The synthesized NPs have flaunted the chemiresistive properties for sensing ammonia and ethanol gases. The SnO2 NPs has exhibited the highest sensing response for test gases at 120°C operating temperature compared to SnO NPs. In addition, the synthesized tin oxide NPs corroborated the substantial anticancer activity by MTT cell viability assay and shows significant in-vitro anticancer activity on lung cancer A549 cells. The evaluation of antimicrobial and antioxidant activities of the tin oxide NPs was also done and demonstrated excellent biocompatibility for the tested biological species. Hence, the synthesized tin oxides NPs become promising candidates to develop physical, chemical and biomedical applications due to their inherent multifunctional characteristics.

Abstract 2085: The specific TLR3-agonist TL-532 induces life-long anti-tumor autovaccination, cross-immunity against unrelated cancers and reverses resistance to immune checkpoint inhibitors

Abstract Background: Toll-Like Receptor 3 (TLR3) is an innate immunity receptor that triggers inflammation by recognizing double stranded RNAs. In the past decades, TLR3-agonists have been used to fight cancer as inducer of type-I interferons and inducer of apoptosis specifically in tumor cells but not in normal cells. No TLR3-agonist has reached the market to date due to lack of manufacturing reproducibility, specificity, activity and/or due to toxicity. In this context, a new family of synthetic, specific and fully defined TLR3-agonist has been rationally designed (WO2019211492). Here we report the preclinical proof-of-concept of TL-532 in non-muscular invasive bladder cancer (NMIBC). Methods: In-vitro 2D and 3D cultures of J82 and RT4 NMIBC versus normal urothelial cells, were used. Freshly resected bladder tumors from patients were sliced and cultured ex vivo for 24 to 48h. In vivo experiments were performed using the ICI-resistant murine syngeneic/ectopic bladder cancer model MBT2, treated by intra- and peri-tumoral injections of TL-532. Results: We demonstrated in vitro, ex vivo and in vivo that TL-532 induced tumor cell death specifically by apoptosis, while it was well tolerated by normal cells, representing a broad in vitro safety margin. Ex vivo and in vivo, this tumor cell death was associated with a tumor microenvironment switch, evidenced by increases in antitumor biomarker secretion (IFN-α, IFN-λ1, IFN-γ, CCL5, CXCL9, CXCL10, CX3CL10), decreases in protumor biomarkers CCL22, sFAS and was associated in vivo with the recruitment and activation of conventional dendritic cells (cDCs) and cytotoxic T-lymphocytes (CTLs) at the tumor site. In vivo activity of TL-532 led to substantial tumor growth inhibition (88%) and delay (370%), translating in 35% complete response (CR) rate and 5.3-fold median survival benefit. Interestingly, among these CRs, 62% (13/21) showed life-long tumor auto-vaccination after 3 consecutive rechallenges at 3, 10 and 30 months. Remarkably, 54% (6/11) of the mice autovaccinated against bladder cancer also demonstrated cross-immunity against an unrelated and poorly immunogenic, syngeneic osteosarcoma cancer cell model (LM8). In addition, TL-532 treatment appeared to decrease the expression of the immune checkpoint PD-L1 on tumor cells ex-vivo and in cDCs in vivo and demonstrated a remarkable ability to reverse the anti-PD-L1 tumor-resistance when combined with the ICI leading to doubling of CR rate. Conclusion: We identified TL-532 as spearhead of a new rationally designed TLR3-agonist family. In monotherapy, it demonstrated substantial tolerance and promising anti-cancer and autovaccinal activity, which included unrelated cancers. TL-532 also demonstrated its remarkable ability to overcome ICI tumor-resistance, thus increasing the clinical landscape for ICI combination treatment. Citation Format: Marc Bonnin, Saïd Ourfali, Mathilde Boucard-Jourdin, Clémence Perret, Chloé Renoux, Nelly Vey, Marc Colombel, Bettina Werlé, Sylvain Thierry. The specific TLR3-agonist TL-532 induces life-long anti-tumor autovaccination, cross-immunity against unrelated cancers and reverses resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2085.

Synthesis and computational studies of potent antimicrobial and anticancer indolone scaffolds with spiro cyclopropyl moiety as a novel design element

The indolones nucleus is the central core to develop new effective anticancer agents and its substitution at the 3-position can affect antitumor activity, 3-spirocyclopropyl-2-oxindoles have attracted the scientist's community to design and develop expedition's strategies towards their construction and explore the potential of this useful scaffold with their newer derivatives in medicinal world. The present paper describes the synthesis of 3-spirocyclopropyl-2-indolone derivatives in three steps via synthesis of ylide leading to methylene-indolinones followed by the formation of the final product spirocyclopropyl oxindole derivatives with improved yields. In this milieu we considered motivating to advance exploration the biological potencies and computational studies of our newly synthesized molecules. The aimed target molecules were screened for antimicrobial and anticancer activities where they exhibited substantial effective antimicrobial activities. Amongst them, potent compound, bromospirocyclopropyl indolone, 6d displayed encouraging MIC ranging from 0.007 to 0.49 μg/mL for gram positive microbes and also substantial anticancer activity with an IC50 of 11.5 μg/mL. Finally, the computational modelling studies were performed to explore structure-activity relationship analysis. Active site of receptor protein shows docking scores of these molecules as - 5.78 kcal/mol and −5.097 kcal/mol for the docked target proteins. The binding energy of the best score is found to be −41.67 kcal/mol to −44.67 kcal/mol. Thus, the present paper efficaciously validated spirocyclopropyl indolone framework for drug candidates as potent anticancer as well as antimicrobial compounds.

Chemical Composition and Cytotoxic Activity of Pistacia atlantica var. kurdica Fruits

Pistacia atlantica var. kurdica (Anacardiaceae) is a major subspecies found in the Kurdistan region of Iraq and has several beneficial bioactivities such as antioxidant, antibacterial, and antiviral. P. atlantica growing in the Kurdistan region is not yet studied phytochemically and pharmacologically. Hence, the goal of the present study is to characterize chemical compounds present in ethanolic extract of P. atlantica fruits by gas chromatography–mass spectroscopy (GC–MS) and to evaluate cytotoxic activity using A549 (human lung cancer) cell lines by (3-4,5 dimethylthiazol-2yl2,5-diphenyl tetrazolium bromide) assay. The GC–MS analysis shows the presence of 33 chemical compounds which constitute about 99.95% of total compounds, and isospathulenol (14.63%), spathulenol (13.45%), α-terpineol (13.28%), limonene (10.92%), terpinolene (10.89%), β-myrcene (6.92%), ethyl pentadecanoate (6.15%), β-pinene (4.98%), and caryophyllene oxide (4.01%) were found as major chemical compounds. P. atlantica inhibits cell proliferation in A549 cell lines in a time (24 h) and dose-dependent manner (0.5–500 µg/mL). After 24 h of treatment with P. atlantica, the cell viability of A549 cell lines ranged from 93.01 ± 5.24 to 57.69 ± 4.15% for concentrations of 0.5–500 µg/mL, respectively. This study expands the knowledge of the chemical composition of P. atlantica fruits and provides scientific evidence for its possible use as an anticancer medicine. The substantial anticancer activity of P. atlantica fruits may be due to the presence of isospathulenol, spathulenol, α-terpineol, limonene, terpinolene, β-myrcene, ethyl pentadecanoate, β-pinene, and caryophyllene oxide.

Development and Evaluation of Repurposed Etoricoxib Loaded Nanoemulsion for Improving Anticancer Activities against Lung Cancer Cells.

In the present work, novel modality for lung cancer intervention has been explored. Primary literature has established the potential role of cyclooxygenase-2 (COX-2) inhibitor in regression of multiple forms of carcinomas. To overcome its poor water solubility and boost anticancer activity, etoricoxib (ETO) was chosen as a therapeutic candidate for repurposing and formulated into a nanoemulsion (NE). The prepared ETO loaded NE was characterized for the surface charge, droplet size, surface morphology, and in vitro release. The optimized ETO loaded NE was then investigated for its anticancer potential employing A549 lung cancer cell line via cytotoxicity, apoptotic activity, mitochondrial membrane potential activity, cell migration assay, cell cycle analysis, Caspase-3, 9, and p53 activity by ELISA and molecular biomarker analysis through RT-PCR test. The developed ETO-NE formulation showed adequate homogeneity in the droplet size distribution with polydispersity index (PDI) of (0.2 ± 0.03) and had the lowest possible droplet size (124 ± 2.91 nm) and optimal negative surface charge (−8.19 ± 1.51 mV) indicative of colloidal stability. The MTT assay results demonstrated that ETO-NE exhibited substantial anticancer activity compared to the free drug. The ETO-NE showed a substantially potent cytotoxic effect against lung cancer cells, as was evident from the commencement of apoptosis/necrotic cell death and S-phase cell cycle arrests in A549 cells. The study on these molecules through RT-PCR confirmed that ETO-NE is significantly efficacious in mitigating the abundance of IL-B, IL-6, TNF, COX-2, and NF-kB as compared to the free ETO and control group. The current study demonstrates that ETO-NE represents a feasible approach that could provide clinical benefits for lung cancer patients in the future.

Green Synthesis of Copper Oxide Nanoparticles Using Coix lacryma jobi Leaves Extract and Screening of its Potential Anticancer Activities

Background: Copper oxide nanoparticles(CuO NPs) have been powerful evidence in several in vitro studies such as cytotoxicity and antimicrobial compared with other metal oxide. Here, we have synthesized green CuO NPs using Coix lacryma jobi leaves extracts.
 Place and Duration of Study: Department of Chemistry Manipur University, Manipur, India and Regional Institute of Medical Sciences, Imphal, India between February 2019 to March 2021.
 Methodology: Green CuO NPs nanoparticles were synthesized from Copper chloride dihydrate (CuCl2.2H2O) using Coix lacryma jobi leaves extract, and the synthesized green CuO NPs were characterized using Field Emission Scanning Electron Microscopy (FESEM) - Energy Dispersive Spectroscopy, IR Spectroscopy, UV-Visible Spectroscopy, Powder X-Ray diffraction Spectroscopy and HR-TEM where FESEM-EDS determined the purity of CuO NPs.
 Results: No other impurities present were observed in EDS, and the PXRD spectra show the crystallite size of CuO NPs with respect to the (002) plane is found to be 25.2 nm, and the presence of CuO NPs at adsorption spectrum with a distinct peak at 282 nm was determined by UV-Visible spectroscopy and the homogenous morphology and crystalline nature of the CuO NPs were determined from TEM micrograph and SAED pattern. In applications, the substantial anticancer activity of green CuO NPs (synthesized using Coix lacryma jobi leaves extract) was proved on human cervical and lung cancer cell lines with IC50 values of 31.88 μg/ml and 15.61 μg/ml, respectively.

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.

One-Pot Green Synthesis of Acridine Alkaloid Derivatives and Screening of in vitro Anti-cancer Activity Against Cdc25b and SHP1.

To develop anti-cancer active pharmaceutical intermediates. Acridone derivatives possess a wide range of pharmacological activities: 1) they intercalate DNA and 2) form a covalent bond with DNA. To screen in vitro anti-cancer activity against Cdc25b and SHP1 of new acridone derivatives and preliminary study on the structure-activity relationship. The synthesis of new acridone derivatives and in vitro evaluation of their anti-cancer activity on Cdc25b and SHP1 was achieved. Natural products that contain acridine structures, such as cystodytin A and acronycine, are isolated from certain marine (tunicates & ascidians, sponges, sea anemones) and plant (bark of Australian scrub ash tree) species. Herein, we report the efficient one-pot green synthesis of twelve novel 3,4-dihydro-1 (2H) acridone derivatives, using montmorillonite K10 as the catalyst and iron/citric acid in water. Also, their inhibitory activity against Cdc25B and SHP1 is examined, in which specific derivatives show enhanced inhibitory activity compared to others. Twelve new acridone derivatives were prepared, starting from 2-nitrobenzaldehyde derivatives and 1, 3-cyclohexanedione derivatives, which exhibited substantial anti-cancer activity against Cdc25b and SHP1 cells. Preliminary studies on the structure-activity relationship have shown the influence of the structural parameters and, in particular, the nature of the substituent on aromatic ring structure and cyclohexanone. Other: Further study on the structure-activity relationship is required.

Enhancement of cytotoxicty of diallyl disulfide toward colon cancer by Eudragit S100/PLGA nanoparticles

According to WHO cancer is the second leading cause of death globally, amounting to about 1 in 6 deaths. Among these, colon cancer is the third leading cause of mortalities worldwide. Current measures for cancer treatment: chemotherapy, radiation, and surgery are accompanied by myriad side effects. In light of a mediocre success of synthetic drugs against cancer exploring the treasure of naturally occurring compounds with anti-cancer activity can be an effective strategy. Diallyl disulfide (DADS), a dietary phytochemical derived from garlic possesses a substantial anti-cancer activity against colon cancer. Nevertheless, its poor water solubility and restricted selectivity towards tumor tissues have limited its clinical applications. Moreover, to deliver intact drugs is another major concern in the treatment of ailments associated with the colon. To address these aforementioned clinically significant issues, we report dual functioning DADS loaded polymeric nanoparticles composed of a combination of Eudragit S100 (ES100) as a pH-sensitive polymer for targeted delivery to colon and poly (lactic-co-glycolic acid) (PLGA) as a biodegradable polymer for sustained release of DADS along with their physicochemical characteristics. Secondly, we report in-vitro cytotoxicity study, cell cycle analysis, and cellular uptake study of DADS loaded polymeric nanoparticles (ES100/PLGA-NPs) in CT26 murine colon carcinoma cells. ES100/PLGA-NPs elucidated higher cell growth inhibition and low IC50 value, in comparison to free DADS. Cellular uptake study exhibited the internalization of ES100/PLGA-NPs. These outstanding data illuminate that the fabricated polymeric nanoparticles as an effective modality for site-specific targeting and its use to augment the efficacy of highly hydrophobic dietary phytochemicals locally in the inflamed colon while minimizing systemic side effects.

Investigations of adsorption behavior and anti-cancer activity of curcumin on pure and platinum-functionalized B12N12 nanocages

Recently boron nitride (BN) nanoparticles have been considered as good carrier candidates in drug delivery systems. Herein, the loading of curcumin (CUR) in different possible states onto a platinum functionalized B12N12 nanocage was studied to improve their solubility and stability using density functional theory (DFT) and time-dependent density functional theory (TDDFT) models by B3LYP and B3PW91 functionals. It was found that the Pt atom in complex I can be strongly bound to B12N12 surface through the B---Pt---N coordination bond or B-Pt-N covalent bond compared to complexes II and III. We investigate the adsorption of CUR onto Pt-B12N12 in gas and solvent (water) phases. IR spectra and UV absorption were computed and investigated in order to identify the most significant alteration that take place as a consequence of interactions between the CUR and Pt-B12N12 nanocage. The decorated Pt on the B12N12 nanocage improves the adsorption of CUR with larger binding energy for both functionals. The strong binding of CUR with Pt-B12N12 can happen by larger charge transfer from the CUR to the cage, which leads to a substantial increase in dipole moment and energy gap change. The study of molecular docking indicates that CUR through its β-diketo group adsorbed on Pt and B atoms of the Pt-B12N12 nanocage and showed the best binding affinity and inhibition potential of tyrosine regulated kinase 2 (DYRK2) and human epidermal growth factor receptor 2 (HER2) as compared with the pure B12N12 nanocage. The results of molecular docking and in silico analysis of absorption, distribution, metabolism, excretion, and toxicity revealed that the chosen complexes agree with the Lipinski Rule and have appropriate pharmacokinetic features which could be used as templates for the development of novel anti-inflammatory agents with substantial anticancer activity.

Limonoids as an effective Anticancer Agent: A Review

Citrus limonoids (CLs) are a group of highly oxygenated terpenoid found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, pumellos, oranges, grapefruits, bergamots, and mandarins. [10] The term limonoids was derived from limonin, which is the first tetranortriterpenoid obtained from bitter principles of citrus [6]. CLs are found as both free aglycones and corresponding -D glucosides, the former mostly occurring in seeds while the latter are formed during fruit maturation. Conversion of agycon to glycon is carried out by two enzymes, uridine diphosphoglucose- limonoid glycosyl t ransferase and limonoid D-ring lactone hydrolase. [8,9]. Glucosides have an open D ring to accommodate an attached glucose moiety; in aglycones the D-ring is closed [9] Citrus fruits are particularly high in a class of phytochemicals known as the limonoids1and recent research suggests that limonoids appearto possess substantial anticancer activity. [7] The present review focused on pharmacological studies of citrus limonoids as an anticancer agent.

Apigenin as Tumor Suppressor in Cancers: Biotherapeutic Activity, Nanodelivery, and Mechanisms With Emphasis on Pancreatic Cancer.

Pancreatic cancer is the most lethal malignancy of the gastrointestinal tract. Due to its propensity for early local and distant spread, affected patients possess extremely poor prognosis. Currently applied treatments are not effective enough to eradicate all cancer cells, and minimize their migration. Besides, these treatments are associated with adverse effects on normal cells and organs. These therapies are not able to increase the overall survival rate of patients; hence, finding novel adjuvants or alternatives is so essential. Up to now, medicinal herbs were utilized for therapeutic goals. Herbal-based medicine, as traditional biotherapeutics, were employed for cancer treatment. Of them, apigenin, as a bioactive flavonoid that possesses numerous biological properties (e.g., anti-inflammatory and anti-oxidant effects), has shown substantial anticancer activity. It seems that apigenin is capable of suppressing the proliferation of cancer cells via the induction of cell cycle arrest and apoptosis. Besides, apigenin inhibits metastasis via down-regulation of matrix metalloproteinases and the Akt signaling pathway. In pancreatic cancer cells, apigenin sensitizes cells in chemotherapy, and affects molecular pathways such as the hypoxia inducible factor (HIF), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1). Herein, the biotherapeutic activity of apigenin and its mechanisms toward cancer cells are presented in the current review to shed some light on anti-tumor activity of apigenin in different cancers, with an emphasis on pancreatic cancer.

Chebulinic acid inhibits MDA-MB-231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy.

Triple-negative breast cancers (TNBC) are highly aggressive and drug resistant accounting for majority of cases with poor outcome. Purified natural compounds display substantial anticancer activity with reduced cytotoxicity providing a new avenue to combat TNBC. Chebulinic acid (CA), a polyphenol derived from the fruits of various medicinal plants has potent anticancer activity. Here, we demonstrate that CA shows significant cytotoxicity against triple negative MDA-MB-231 cells. CA exhibited cytotoxicity to MDA-MB-231 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Further, CA mitigated MDA-MB-231 cells viability and proliferation as shown by reduced live cell count, crystal violet staining, colony formation assay, soft agar assay and cell cycle analysis. Wound healing assay and trans-well migration assay demonstrated that CA significantly inhibited migration of MDA-MB-231 cells. Also reduced MMP9 expression was observed in CA-treated cells by gelatin zymography. CA negatively regulated mesenchymal characteristics of MDA-MB-231 cells demonstrated by F-actin staining and reduced expression of N-cadherin by confocal microscopy and western blot analysis. Annexin V/propidium iodide (PI) and active caspase-3 staining showed that CA was able to induce apoptosis in MDA-MB-231 cells but did not activate caspase-3. Two-dimensional gel electrophoresis based proteomic analysis demonstrated that CA regulated proteins belonging to the oxidative stress pathway, apoptotic pathway and proteins with antiproliferative activity. Western blot analysis analysis revealed that CA negatively regulated superoxide dismutase 1 (SOD1) and enhanced oxidative stress in MDA-MB-231 cells. SOD1 in-gel activity assay also showed reduced SOD1 activity upon CA treatment. Overexpression studies with GFP-LC3 and tandem tagged RFP-GFP-LC-3 also demonstrated enhanced autophagy upon CA treatment.

Long-term use of combined conventional medicine and Chinese herbal medicine decreases the mortality risk of patients with lung cancer

BackgroundWe explored the effect of Chinese herbal medicine (CHM) on the long-term survival of lung cancer patients and hazard ratio (HR) and to analyse CHM herbs and formulas for lung cancer treatment. MethodsWe conducted a retrospective cohort study on diagnosed lung cancer patients in 2003–2016 from Taipei and Dalin Tzu Chi General Hospital Cancer Registry Database and from outpatient database from Chinese Medicine and Conventional Medicine Department. We categorised the patients into CHM user and CHM nonuser groups according to the CHM consumption time. After passing the proportional hazard assumption, we used the Cox PH model to calculate the groups’ survival hazard ratio (HR) and examine the statistical difference and effect of CHM on lung cancer survival. ResultsWe classified 2557 lung cancer patients into 1643 CHM nonusers and 228 CHM users. The CHM users had lower mortality than the CHM nonusers. With the multivariable Cox model, we observed that the CHM use was associated with 35% lower risk of mortality (adjusted HR: 0.65; 95% confidence interval: 0.51-0.76). Continuous CHM use of >180 days may further lessen the mortality risk by 64%. Finally, eight herbs and two formulas could significantly lower the mortality. After pairing the eight herbs for analysis, seven combinations could reduce the mortality better than only using one herb. ConclusionCHM users had significantly lower mortality than CHM nonusers. The longer the CHM use, the more the mortality HR declined. Glehnia littoralisF. Schmidt ex Miq., Polyporus umbellatus(Pers.) Fries and Trichosanthes kirilowii Maxim. possess a highly substantial anticancer activity compared with other herbs.

Optimised synthesis of a nitroCBI hypoxia-activated prodrug with substantial anticancer activity

An optimised synthesis of a hypoxia-activated anticancer prodrug related to the duocarmycin family of natural products is described. The improved 10-step synthesis increases the overall yield from 4.4% to over 40% while requiring just 2 chromatography-based purifications. The most significant improvements optimise the isomer distribution in a key chlorosulfonylation reaction, and facilitate the removal of tin residues from a tributyltin hydride-mediated radical reaction. Improved preparations of two side chains are also reported. The new method provides practical access to sufficient material to support advanced efficacy and toxicology assessments.

A research update on the anticancer effects of bufalin and its derivatives.

Bufalin (BF) is a cardiotonic steroid that has recently been found to have substantial anticancer activity; however, more efforts should be directed toward clarifying the detailed molecular mechanisms underlying this activity. BF could exert its anticancer effect by inducing apoptosis in various human cancer cells and thus triggering autophagic cancer cell death. The anti-inflammatory activities of BF are potentially important for its anticancer functions. Notably, some promising synthetic BF derivatives, including poly (ethylene glycol)-based polymeric prodrug of BF and BF211, have shown potent anticancer activity. Additionally, clinical trials regarding the use of BF-related agents in patients have supported the positive effect of BF as an anticancer treatment. Currently, large-scale randomized, double-blind, placebo or positive drug parallel controlled studies are required to confirm the anticancer potential of BF in various cancer types in the clinical setting. The present review will evaluate the potential mechanisms mediated by BF in intracellular signaling events in cancer cells and various promising BF derivatives that may have greater anticancer activity, thereby clarifying BF-mediated anticancer effects. The experimental and clinical results reviewed strongly emphasize the importance of this topic in future investigations.