Cancer Cell PANC-1 Research Articles

Studying the Anti-Tumor Effects of siRNA Gene Silencing of Some Metabolic Genes in Pancreatic Ductal Adenocarcinoma.

Earlier diagnosis and advances in treatment strategies have increased the average survival of cancer patients over the last decades. Despite the increased number of new anti- neoplastic agents, there has been no adequate therapy for intricate malignancies, such as pancreatic cancer. Cancer metabolism is the main building block standing behind cancer promotion and progression, even in the presence of a harsh environment. Targeting metabolic pathways, such as glycolysis and pentose phosphate pathway, are regarded as a promising new strategy for cancer treatment. The current study aimed to investigate the effects of knocking-down pancreatic cancer glycolytic and pentose phosphate pathway's regulators (HIF-1α, ARNT, PFKFB4, and RBKS) on cell's viability and resistance to Gemcitabine and Doxorubicin, using small interference RNA. The human pancreatic ductal adenocarcinoma cell line, Panc-1, was used to study the anti-proliferative activity of targeting HIF-1α, ARNT, PFKFB4, and RBKS mRNAs by transfection with small interference RNAs, alone and in combination. The transfected cells were also treated with Doxorubicin and Gemcitabine to study the relationship between the concerned genes and the resistance of Panc-1 cells to these drugs. The effect on cell proliferation was determined using a colorimetric assay and Inhibitory Concentration ((IC50) calculation. A cross-talk study was done to investigate the silencing effect of one of the above genes on the expression of others using Real Time-Polymerase Chain Reaction. In vitro transfection with small interference-RNAs, siHIF-1α, siPFKFB4, and siARNT decreased tumor cell proliferation with a maximum effect shown by siPFKFB4; but there was no anti- proliferative effect with RBKS silencing. Suppression of transcription of HIF-1α, ARNT, PFKFB4, and RBKS sensitize pancreatic cancer cells, Panc-1, to Doxorubicin and Gemcitabine. This study demonstrated the major tumor-promoting and progressive effects of PFKFB4, while HIF-1α and ARNT had modulator effects in pancreatic cancer cells (Panc-1). RBKS had a chemo-resistant role, justifying its enhanced expression in Panc-1 cells, but not a proliferative one. Silencing of all genes of interest decreased Doxorubicin and Gemcitabine's resistance and improved their antitumor effect Din the pancreatic cancer cell line, Panc-1.

Dactylospenes A-E, Sesterterpenes from the Marine Sponge Dactylospongia elegans.

Chemical investigation on a marine sponge, Dactylospongia elegans, yielded five new γ-oxygenated butenolide sesterterpene derivatives, dactylospenes A–E (1–5), as well as two known biosynthetically related compounds, luffariellolide (6) and furospinosulin B (7). The structures of these compounds were elucidated on the basis of their spectroscopic data, experimental and calculated electronic circular dichroism (ECD) analysis, as well as comparison of the NMR data with those of known analogs. These metabolites are the first γ-oxygenated butenolide sesterterpenes to be reported from this genus. These compounds were evaluated in antimicrobial, anti-inflammatory, and cytotoxic assays. Only compounds 1, 3, and 6 exhibited moderate cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cancer cell lines with IC50 values in the range of 2.11–13.35 μM. Furthermore, compound 2, without cytotoxicity, exhibited significant inhibitory effects (inhibitory rate 77.5%) on nitric oxide production induced by lipopolysaccharide at 10 μM.

Tumor suppressive activities of solvatochromic 3,3'-azadimethylene dinaphthospiropyran in colon cancer model.

Spiropyrans have been extensively investigated because of their thermo- and photochromic characteristics, but their biotherapeutic properties have not been explored much. We report anti-proliferative properties of a novel 3,3'-azadimethylene dinaphthospiropyran 11. Dibenzospiropyrans and dinaphthospiropyrans were synthesized by a simple and expedient method using acid-catalyzed aldol condensation of salicylaldehyde and 2-hydroxy-1-naphthaldehyde, respectively, with cyclic ketones. Together with structural elucidation by 2D NMR and X-ray crystallography studies, we provide a putative mechanism for their formation. Compound 11 showed solvatochromism and exhibited altered spectral characteristics depending on the pH. In acidic conditions, 11 remains in open form, whereas upon alkalinization it reverts back to closed form. Based on the in vitro anti-proliferative activity in H441, HCT-116, MiaPaCa-2, and Panc-1 cancer cell lines, 11 was submitted to further investigation. It reduced HCT116 colonosphere formation and demonstrated induction of caspase cascade, suggesting apoptosis. In vitro proliferation assays also suggested that HCl and trifluoroacetate salts of 11 are more effective. Treatment of mice carrying HCT-116 xenografts with 11 (5µg/day, intraperitoneal for 3weeks) suppressed tumor growth by 62%. Overall, the results reveal a new series of structurally complex, but relatively easy to synthesize molecules of which compound 11 represents a lead for anticancer development.

Anticancer and therapeutic potential of Delonix regia extract and silver nanoparticles (AgNPs) against pancreatic (Panc-1) and breast (MCF-7) cancer cell

Delonix regia (L.) (Caesalpiniaceae) is one of the plants that have been used for centuries to prevent cancer. D. regia has been described as a strong anti-inflammatory, antibacterial, and analgesic. Also, the cytotoxicity of this plant has been proved due to its flavonoid compounds. Besides, silver (Ag) nanoparticles have been proved to be promising in cancer treatment. The synergistic effect of medicinal plant extracts with silver antibacterial nanoparticles on cancer cell inhibition was investigated. Cytotoxic effect of D. regia extract with silver NPs on MCF-7 and Panc-1 cancer cells was investigated by cell viability analysis, morphological changes, apoptosis induction, and TUNEL assay. Results showed the cells treated with D. regia extract containing AgNPs exhibited a considerable reduction in viability percent in comparison with control cells. Analysis of MTT demonstrated that the IC50 value of D. regia extract and AgNPs on both cell lines observed in 0.5 mg/mL for 24 h. The results demonstrated that the maximum inhibition of both cell lines growth was observed in 1.5 mg/L and 0.2 mg/L in the presence with D. regia and AgNPs, respectively. Also, morphological characteristics of cells indicated that D. regia extract and silver NPs induce cell death by apoptosis and it is confirmed by TUNEL assay. Interestingly, D. regia extract and Ag NPs had no significant cytotoxicity against normal cells. It can be concluded that Delonix regia plant and silver nanoparticles have an inhibitory potential on two cancer cell lines, but in the use of synergism of D. regia extract and AgNPs, the induction of apoptosis in MCF-7 and Panc-1 was increased. Interestingly, in normal cells, no significant negative effect was observed as control.

Role of Poly [ADP-ribose] Polymerase 1 in Activating the Kirsten ras (KRAS) Gene in Response to Oxidative Stress.

In pancreatic Panc-1 cancer cells, an increase of oxidative stress enhances the level of 7,8-dihydro-8-oxoguanine (8OG) more in the KRAS promoter region containing G4 motifs than in non-G4 motif G-rich genomic regions. We found that H2O2 stimulates the recruitment to the KRAS promoter of poly [ADP-ribose] polymerase 1 (PARP-1), which efficiently binds to local G4 structures. Upon binding to G4 DNA, PARP-1 undergoes auto PARylation and thus becomes negatively charged. In our view this should favor the recruitment to the KRAS promoter of MAZ and hnRNP A1, as these two nuclear factors, because of their isoelectric points >7, are cationic in nature under physiological conditions. This is indeed supported by pulldown assays which showed that PARP-1, MAZ, and hnRNP A1 form a multiprotein complex with an oligonucleotide mimicking the KRAS G4 structure. Our data suggest that an increase of oxidative stress in Panc-1 cells activates a ROS-G4-PARP-1 axis that stimulates the transcription of KRAS. This mechanism is confirmed by the finding that when PARP-1 is silenced by siRNA or auto PARylation is inhibited by Veliparib, the expression of KRAS is downregulated. When Panc-1 cells are treated with H2O2 instead, a strong up-regulation of KRAS transcription is observed.

Abstract 5376: Label-free classification of cells based on supervised machine learning of subcellular structures for negative selection of circulating tumor cells

Abstract Background: Circulating tumor cells (CTCs) are used as a liquid biopsy target in the treatment of cancer patients and are important for personalized medicine. Most CTC detection technologies are based on their surface markers such as EpCAM and cytokeratin. However, those positive selection methodologies appear to count only some CTCs because invasive tumor cells tend to change their surface markers during progression. Because the vast majority of nucleated cells circulating in the bloodstream are white blood cells (WBCs), eliminating WBCs from circulation is an efficient method to purify CTCs by negative selection. In this study, we demonstrate the development of cell recognition by computer vision technologies for pattern recognition based on the morphological features of live cells. Materials and methods: Blood samples obtained from healthy volunteers, and five cancer cell lines, SW480, DLD-1, HCT116, Panc-1, and HepG2 were imaged by quantitative phase microscopy (QPM), which provides morphological information without staining quantitatively in terms of optical thickness of cells. Subcellular features were then extracted from the obtained images as training data sets for the machine learning. WBC recognition algorithm was developed using computer vision technologies for pattern recognition based on the histogram-oriented gradient (HOG) features extracted from QPM images (QPIs). Results: We observed WBCs and five cell line cells by QPM, extracted certain features from the obtained images as training data for pattern recognition, and created an algorithm to differentiate WBCs from cell lines. The obtained algorithm successfully differentiated WBCs from cell lines (AUC=0.996). This image recognition methods was then applied to QPIs of the cells flowing in the chamber, and properly differentiated WBCs from cell line cells flowing in the chamber (AUC=0.99). Finally, we applied this method to blood samples obtained from a healthy volunteer and patients with advanced cancer, and identified CTC fractions which were much higher in blood of a cancer patient than that of a healthy volunteer. In addition, in esophageal cancer patients who received neoadjuvant chemotherapy followed by surgery, CTC fractions changed over time consistently with therapeutic effects. Conclusions: We developed a novel method for label-free image identification of live cells by computer vision technologies for pattern recognition based on the features of QPIs. Our novel method is expected to apply to detecting CTCs in a noncytotoxic manner, thus providing good opportunities for studying intact CTCs Citation Format: Hirotoshi Kikuchi, Amane Hirotsu, Yusuke Ozaki, Hidenao Yamada, Daisuke Yamashita, Shigetoshi Okazaki, Yukio Ueda, Tomohiro Matsumoto, Yoshihiro Hiramatsu, Kinji Kamiya, Yoshifumi Morita, Takanori Sakaguchi, Hiroyuki Konno, Hiroya Takeuchi. Label-free classification of cells based on supervised machine learning of subcellular structures for negative selection of circulating tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5376.

Targeting Gemcitabine hydrochloride to tumor microenvironment through stimuli-responsive Nano-conjugate: Synthesis, characterization, and in vitro assessment

The study revolves around synthesizing stimuli-responsive drug-polymer conjugate of Gemcitabine hydrochloride and PNIPAAm-co-AAc and to investigate the delivery of Gemcitabine to cancerous cells by the formulation of stimuli-responsive Gem-conjugate. Gemcitabine HCl conjugated to a thermoresponsive polymer was undergone through the amine group at the N4 position of Gemcitabine hydrochloride linked with the carboxylic group of the stimuli-responsive polymer, leading to the construction of amide linkage amongst the drug and polymer. The subsequent Gem-conjugate was characterized by several analytical methods viz. Elemental, DSC, TGA, XRD, FESEM, TEM, DLS and 1H NMR. Finally, in vitro cytotoxicity assay was carried out on Panc-1 cancer cell lines. The prepared stimuli-responsive Gemcitabine nanoconjugate was found to be 55.05 nm in size with a capacity to release 80.72% drug over a period of 24 h in a medium of pH 5.0 following Fickian release kinetics. The cytotoxicity assay revealed that nanoconjugate notably inhibited the growth of Panc-1 cells compared to the free drug in a dose-dependent manner. The CLSM study revealed that Gem-conjugate induces more apoptosis to Panc-1 cell as compared to the native drug. The stimuli-responsive nano conjugate was found stable at 25 °C in dark environment. Overall, the data suggest that Gemcitabine HCl conjugated to a stimuli-responsive polymer can intensify the delivery of Gemcitabine to Panc-1 cancer cell lines, which might hold substantially proven potential in the treatment pancreatic cancer. The conjugate holds an alternative direction for further applications of Gemcitabine hydrochloride.

Salidroside inhibits proliferation, migration and invasion of human pancreatic cancer PANC1 and SW1990 cells through the AKT and ERK signaling pathway.

Salidroside is the main compounds extracted from the Chinese medicine Rhodiola rosea and has many pharmacological effects, including anti-tumor effects. However, the role of salidroside in human pancreatic cancer remains poorly known. Thus, the focus of this study was to evaluate the inhibitory effect of purified salidroside on human pancreatic cancer cells and its underlying molecular mechanisms. PANC1 and SW1990 cells were incubated with various concentrations of salidroside, and CCK-8 assay, colony formation, apoptosis, migration and invasion, western blot were conducted. As a result, it was found that salidroside significantly inhibited pancreatic cancer cells viability, proliferation, migration and invasion, and also induced cell apoptosis. Furthermore, we also detected that salidroside inhibited pancreatic cancer cells by downregulating the AKT and ERK signaling pathways. In conclusion, these findings suggest that salidroside may be a promising candidate for the development of a therapy of human pancreatic cancer.

Arginine-Based Poly(I:C)-Loaded Nanocomplexes for the Polarization of Macrophages Toward M1-Antitumoral Effectors.

Background: Tumor-associated macrophages (TAMs), with M2-like immunosuppressive profiles, are key players in the development and dissemination of tumors. Hence, the induction of M1 pro-inflammatory and anti-tumoral states is critical to fight against cancer cells. The activation of the endosomal toll-like receptor 3 by its agonist poly(I:C) has shown to efficiently drive this polarization process. Unfortunately, poly(I:C) presents significant systemic toxicity, and its clinical use is restricted to a local administration. Therefore, the objective of this work has been to facilitate the delivery of poly(I:C) to macrophages through the use of nanotechnology, that will ultimately drive their phenotype toward pro-inflammatory states.Methods: Poly(I:C) was complexed to arginine-rich polypeptides, and then further enveloped with an anionic polymeric layer either by film hydration or incubation. Physicochemical characterization of the nanocomplexes was conducted by dynamic light scattering and transmission electron microscopy, and poly(I:C) association efficiency by gel electrophoresis. Primary human-derived macrophages were used as relevant in vitro cell model. Alamar Blue assay, ELISA, PCR and flow cytometry were used to determine macrophage viability, polarization, chemokine secretion and uptake of nanocomplexes. The cytotoxic activity of pre-treated macrophages against PANC-1 cancer cells was assessed by flow cytometry.Results: The final poly(I:C) nanocomplexes presented sizes lower than 200 nm, with surface charges ranging from +40 to −20 mV, depending on the envelopment. They all presented high poly(I:C) loading values, from 12 to 50%, and great stability in cell culture media. In vitro, poly(I:C) nanocomplexes were highly taken up by macrophages, in comparison to the free molecule. Macrophage treatment with these nanocomplexes did not reduce their viability and efficiently stimulated the secretion of the T-cell recruiter chemokines CXCL10 and CCL5, of great importance for an effective anti-tumor immune response. Finally, poly(I:C) nanocomplexes significantly increased the ability of treated macrophages to directly kill cancer cells.Conclusion: Overall, these enveloped poly(I:C) nanocomplexes might represent a therapeutic option to fight cancer through the induction of cytotoxic M1-polarized macrophages.

Effect of the botanical compound LCS102 on innate immunity.

Innate immunity serves an important role in the healthy population, providing surveillance and protection against infections. Chemotherapy suppresses the body's immune system, including neutrophil and natural killer (NK) cell numbers and activity. This leads to an increased risk of infection which often requires the reduction or even discontinuation of the chemotherapeutic regimens. The botanical formula LCS102 was designed to stimulate the body's immune system. The effect of the formula on innate immunity was examined in human blood samples, as were its effect on the anti-cancer activity of chemotherapeutic agents on human cancer cells. Blood samples drawn from 20 volunteers (19 healthy subjects; 1 patient with breast cancer undergoing chemotherapy) and were exposed to LCS102. The effects on neutrophil and NK cell activity were tested using FACS. The anti-cancer effects of LCS102 were tested on T24, A549, MCF7, PANC-1 and U2OS human cancer cell lines, as were the effects of the formula on doxorubicin, Taxol, etoposide and cisplatin-treated cells using a sulforodamine B viability assay. LCS102 was shown to significantly increase the percentage of activated neutrophils and NK cells in the blood samples tested. The formula did not inhibit the cytotoxic effects of the chemotherapeutic agents, and in certain cases increased their anti-cancer activity. Further research is required to improve our understanding of the clinical value of LCS102; however, it may serve as an adjuvant during chemotherapy, to reduce the effects of chemotherapy on innate immunity.

Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines

Cisplatin (CIS) is widely applied as an anticancer drug for various cancer types, including liver, breast, colorectal, and pancreatic cancers; however, its usage is limited due to side effects. We investigated whether combined therapy of Graviola (Annona muricata) leaves extract (GLE) and CIS could reduce CIS doses without decreasing its anticancer potential. The MCF7, HepG2, CaCo2, or PANC1 cells were divided into four groups for each cell line as follows: group1 (G1): untreated cells, G2: cells treated with GLE, G3: cells treated with CIS, and G4: cells treated with GLE, after 2 h treated with CIS. All combinations were prepared as non-constant ratio from GLE. The cytotoxicity, gene expression, cell cycle arrest were determined by MTT assay, real-time PCR, and cell flow cytometry, respectively. Treatment with GLE and/or CIS-induced cytotoxic effect on HepG2, MCF7, CaCo2, and PANC1 cancer cells with the best effect of combined therapy. All twelve non-constant ratio combinations (GLE + CIS) for each cell line resulted in a significant higher cytotoxic effect than single drug treatment. The combination index (CI) values for all combinations were less than one, indicating the presence of synergistic cytotoxic effect between CIS and GLE against the four cancer cell lines. This anticancer effect was triggered through mitochondrial-dependent apoptosis with the downregulation of caspase3, Bax, and p53 and upregulation of Bcl2. GLE also shifted G0/G1 phase of cell cycle arrest induced by CIS to S and G2/M phases. Interestingly, this combined therapy did not affect oxidative stress (indicated by higher malondialdehyde level and lower activities of SOD, CAT, and GPX) induced by CIS; however, it downregulated the expression of MAPK1 and multidrug resistance gene MDR1. These results demonstrate that Graviola leaves extract optimizes the antitumor potential of cisplatin and could be utilized as a natural adjuvant to decrease cisplatin side effects.

New antimicrobial and cytotoxic benzofuran glucoside from Senecio glaucus L

The ethyl acetate fraction of the dried aerial parts of Senecio glaucus L. exhibited significant antimicrobial activity against some of selected bacteria and fungi. Also, it showed potent cytotoxicity against PANC-1 cancer cell lines under glucose deficient medium. The ethyl acetate fraction was subjected to different chromatographic techniques for isolation of the bioactive compounds. A new benzofuran glucoside; 2,3-dihydro-3β-hydroxyeuparin 3-O-glucopyranoside (1) was isolated. Additionally, two known flavonoid compounds isorhamentin 3-O-β-D-glucoside (2), and isorhamentin 3-O-β-D-rutinoside (3) were first identified in S. glaucus. Compound 1 exhibited potent antimicrobial activities against two Gram-positive bacteria, one Gram-negative bacteria, and two fungi. Also, it displayed potent cytotoxic activity against PANC-1 cancer cell lines under glucose deficient medium (IC50 7.5 μM). However, the isolated flavonoid glycosides (2 & 3) showed moderate antimicrobial activities against two Gram-positive bacteria, two Gram-negative bacteria, four fungi, and did not show any cytotoxic activity against PANC-1.

First Total Synthesis and in Vitro Cytotoxicities of Flavesines G and J.

The first total synthesis of flavesines G and J, natural products exhibiting antiviral activity against hepatitis B virus, is described. A robust, protecting-group-free route starting from commercially available natural product 9-azajulolidine allowed us to obtain the title compounds in a four- and five-step sequence accordingly. Flavesines G and J exhibit micromolar cytotoxicity in A549, MCF-7, HepG2, PANC-1, and HL-60 cancer cell lines.

Ultrasound-Activated Cascade Effect for Synergistic Orthotopic Pancreatic Cancer Therapy.

SummaryIn some malignant tumor, especially for pancreatic tumor, poor solid-tumor penetration of nanotherapeutics impedes their treatment efficacy. Herein, we develop a polymer-peptide conjugate with the deep tissue penetration ability, which undergoes a cascade process under ultrasound (US), including (1) the singlet oxygen 1O2 is generated by P18, (2) the thioketal bond is cleaved by the 1O2, (3) the departure of PEG chains leads to the in situ self-assembly, and (4) the resultant self-assembled PK nanoparticles show considerable cellular internalization. Owing to the synergistic effect of US on increasing the membrane permeability, the endocytosis and lysosome escape of PK nanoparticles are further enhanced effectively, resulting in the improved therapeutic efficacy. Thanks to the high tissue-penetrating depth and spatial precision of US, PTPK presents enhanced tumor inhibition in an orthotopic pancreatic tumor model. Therefore, the US-activated cascade effect offers a novel perspective for precision medicine and disease theranostics.

A modified arginine-depleting enzyme NEI-01 inhibits growth of pancreatic cancer cells

Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

Lipidomics reveals carnitine palmitoyltransferase 1C protects cancer cells from lipotoxicity and senescence

Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C (CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1, MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis. Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene mRNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.

New azaphilones, phomopsones A-C with biological activities from an endophytic fungus Phomopsis sp. CGMCC No.5416

Three undescribed azaphilones, phomopsones A-C (1–3) and two known azaphilones (4–5) were isolated from the culture of endophytic fungus Phomopsis sp. CGMCC No.5416 from the stems of Achyranthes bidentata. Their structures were determined by spectroscopic analysis (HRESIMS, 1D and 2D NMR), and the absolute configurations were determined by CD spectroscopy. Compounds 2 and 3 showed significant inhibitory activities against HIV-1 with against HIV-1 with IC50 values of 7.6 and 0.5 μmol/L, respectively. Compounds 2 and 3 also displayed moderate cytotoxicity with CC50 values of 3.2–303 μmol/L against A549, MDA-MB-231 and PANC-1 cell lines. Moreover, compound 3 can induce the early apoptosis of PANC-1 cancer cells with the apoptosis rate of 28.54%.

Application of non-invasive low-intensity pulsed electric field with thermal cycling-hyperthermia for synergistically enhanced anticancer effect of chlorogenic acid on PANC-1 cells.

Most existing cancer treatments involve high-cost chemotherapy and radiotherapy, with major side effects, prompting effort to develop alternative treatment modalities. It was reported that the combination of thermal-cycling hyperthermia (TC-HT) and phenolic compound exhibited a moderate cytotoxic effect against human pancreatic cancer PANC-1 cells. In this study, we investigate the efficacy of triple combination in PANC-1 cancer cells by adopting low-intensity pulsed electric field (LIPEF) to couple with TC-HT and CGA (chlorogenic acid). The study finds that this triple combination can significantly impede the proliferation of PANC-1 cells, with only about 20% viable cells left after 24h, whereas being non-toxic to normal cells. The synergistic activity against the PANC-1 cells was achieved by inducing G2/M phase arrest and apoptosis, which were associated with up-regulation of p53 and coupled with increased expression of downstream proteins p21 and Bax. Further mechanism investigations revealed that the cytotoxic activity could be related to mitochondrial apoptosis, characterized by the reduced level of Bcl-2, mitochondrial dysfunction, and sequential activation of caspase-9 and PARP. Also, we found that the triple treatment led to the increase of intracellular reactive oxygen species (ROS) production. Notably, the triple treatment-induced cytotoxic effects and the elevated expression of p53 and p21 proteins as well as the increased Bax/Bcl-2 ratio, all could be alleviated by the ROS scavenger, N-acetyl-cysteine (NAC). These findings indicate that the combination of CGA, TC-HT, and LIPEF may be a promising modality for cancer treatment, as it can induce p53-dependent cell cycle arrest and apoptosis through accumulation of ROS in PANC-1 cells.

Glycofullerenes as non-receptor tyrosine kinase inhibitors- towards better nanotherapeutics for pancreatic cancer treatment

The water-soluble glycofullerenes GF1 and GF2 were synthesized using two-step modified Bingel-Hirsch methodology. Interestingly, we identified buckyballs as a novel class of non-receptor Src kinases inhibitors. The evaluated compounds were found to inhibit Fyn A and BTK proteins with IC50 values in the low micromolar range, with the most active compound at 39 µM. Moreover, we have demonstrated that formation of protein corona on the surface of [60]fullerene derivatives is changing the landscape of their activity, tuning the selectivity of obtained carbon nanomaterials towards Fyn A and BTK kinases. The performed molecular biology studies revealed no cytotoxicity and no influence of engineered carbon nanomaterials on the cell cycle of PANC-1 and AsPC-1 cancer cell lines. Incubation with the tested compounds resulted in the cellular redox imbalance triggering the repair systems and influenced the changing of protein levels.

Three novel chromanones with biological activities from the endophytic fungus Phomopsis CGMCC No. 5416.

Three undescribed chromanones (1-3) and two known chromanones (4 and 5) were isolated from the culture of endophytic fungus Phomopsis CGMCC No. 5416 from the stems of Achyranthes bidentata. Their structures were determined by spectroscopic analysis. Compounds 1 and 2 showed inhibitory activities against HIV-1 with IC50 values of 20.4 and 32.5 μg ml-1, respectively. Compounds 1-3 displayed moderate cytotoxicity with CC50 values of 36.5-79.3 μg ml-1 against A549, MDA-MB-231, and PANC-1 cell lines. Moreover, compound 3 can induce the early apoptosis of PANC-1 cancer cells with the apoptosis rate of 10.52%.