Preferentially Cytotoxic Constituents of Andrographis paniculata and their Preferential Cytotoxicity against Human Pancreatic Cancer Cell Lines

In the course of our search for anticancer agents based on a novel anti-austerity strategy, we found that the 70% EtOH extract of the crude drug Andrographis Herba (aerial parts of Andrographis paniculata), used in Japanese Kampo medicines, killed PANC-1 human pancreatic cancer cells preferentially in nutrient-deprived medium (NDM). Phytochemical investigation of the 70% EtOH extract led to the isolation of 21 known compounds consisting of six labdane-type diterpenes (11, 15, 17-19, 21), six flavones (5, 7, 10, 12, 14, 20), three flavanones (2, 6, 16), two sterols (3, 8), a fatty acid (1), a phthalate (4), a triterpene (9), and a monoterpene (13). Among them, 14-deoxy-11,12-didehydroandrographolide (17) displayed the most potent preferential cytotoxicity against PANC-1 and PSN-1 cells with PC50 values of 10.0 μM and 9.27 μM, respectively. Microscopical observation, double staining with ethidium bromide (EB) and acridine orange (AO), and flow cytometry with propidium iodide/annexin V double staining indicated that 14-deoxy-11,12-didehydroandrographolide (17) triggered apoptosis-like cell death in NDM with an amino acids and/or serum-sensitive mode.

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Anti-austeritic Constituents of the Congolese Medicinal Plant Aframomum melegueta

Natural Product Communications ◽

10.1177/1934578x1501000650 ◽

2015 ◽

Vol 10 (6) ◽

pp. 1934578X1501000

Author(s):

Dya Fita Dibwe ◽

Suresh Awale ◽

Hiroyuki Morita ◽

Yasuhiro Tezuka

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Medicinal Plant ◽

Anticancer Agents ◽

Democratic Republic ◽

Democratic Republic Of Congo ◽

Human Pancreatic Cancer ◽

Cytotoxic Compound ◽

Pancreatic Cancer Cells ◽

Phytochemical Investigation

In the course of our search for anticancer agents based on a novel anti-austerity strategy, we found that the CHCl3 extract of the roots of Aflamomum melegueta (Zingiberaceae), collected in the Democratic Republic of Congo, killed PANC-1 human pancreatic cancer cells preferentially in nutrient-deprived medium (NDM). Phytochemical investigation of the CHCl3 extract led to the isolation of seven known compounds [(-)-buplerol (1), (-)-arctigenin (2), ( E)-14-hydroxy-15-norlabda-8(17),12-dien-16-al (3), labda-8(17),12-dien-15,16-dial (4), 16-oxo-8(17),12( E)-labdadien-15-oic acid (5), 5-hydroxy-7-methoxyflavone (6), and apigenin (7)]. In addition to the previously reported preferentially cytotoxic compound, (-)-arctigenin (2, PC50 0.5 μM), (-)-buplerol (1) also displayed potent preferential cytotoxicity with a PC50 value of 8.42 pM and triggered apoptosis-like PANC-1 cell death in NDM.

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Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

International Journal of Molecular Sciences ◽

10.3390/ijms22041870 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1870

Author(s):

Shin Hamada ◽

Ryotaro Matsumoto ◽

Yu Tanaka ◽

Keiko Taguchi ◽

Masayuki Yamamoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Progression ◽

Anticancer Agents ◽

Therapeutic Interventions ◽

Human Pancreatic Cancer ◽

Pancreatic Cancers ◽

Pancreatic Cancer Cells ◽

Nrf2 Activation

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

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Effect of triptolide on gemcitabine-mediated apoptosis in pancreatic cancer cell lines.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22043 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22043-e22043

Author(s):

Wei Wang ◽

Wenjie Lin

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Drug ◽

Pancreatic Cancer Cell ◽

Chinese Herb ◽

Annexin V ◽

Cancer Cell Lines ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

e22043 Background: Pancreatic cancer is notorious for its resistance to anticancer drug. gemcitabine, the most effective anticancer drug currently available for palliative chemotherapy in pancreatic cancer patients, hardly achieves clinically satisfactory response rates. Therefore, it is urgent to develop novel agents that overcome drug resistance of pancreatic cancer. In this study, we demonstrated for the first time that triptolide, a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, can enhance gemcitabine-mediated apoptosis in human pancreatic cancer cell lines (AsPC-1 and PANC-1). Methods: Pancreatic cells were treated with gemcitabine or triptolide alone, and combination of them, cell viability was measured by MTT, and apoptotic cells were assessed by flow cytometry for Annexin V/PI staining and western blot for cleaved caspase-3, 8, 9 and PARP. To explore the mechanism of enhancement of triptolide and gemcitabine, proteomic approach was used to screen the related apoptosis factors. Results: Triptolide demonstrated toxicity on pancreatic cancer cell lines with the IC50 of 25-40 nM. The combination of triptolide (IC30 concentration) and gemcitabine enhanced the cytotoxicity significantly compared to gemcitabine alone. Combination index (CI) indicated the effect of triptolide plus gemcitabine was synergistic. Furthermore, pancreatic cancer cells treated with triptolide plus gemcitabine exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with gemcitabine alone. In the mechanism study, vimentin, a mesenchymal marker, was screened out to be correlated with enhanced apoptosis induced by triptolide plus gemcitabine. Conclusions: 1) Triptolide has a potent therapeutic effect on pancreatic cancer cell lines; 2) the combination of triptolide with gemcitabine enhances the apoptosis in vitro, low concentration of TPL showed synergistic effect with gemcitabine; 3) The enhanced apoptosis induced by triptolide plus gemcitabine is correlated with vimentin expression inhibited by triptolide.

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Chelidonine Induces Apoptosis via GADD45a-p53 Regulation in Human Pancreatic Cancer Cells

Integrative Cancer Therapies ◽

10.1177/15347354211006191 ◽

2021 ◽

Vol 20 ◽

pp. 153473542110061

Author(s):

Hyun-Jin Jang ◽

Jae Ho Yang ◽

Eunmi Hong ◽

Eunbi Jo ◽

Soon Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Annexin V ◽

Inhibitory Effect ◽

Human Pancreatic Cancer ◽

Mrna Levels ◽

Chelidonium Majus ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Anti Cancer

Chelidonium majus has been used as a traditional medicine in China and western countries for various diseases, including inflammation and cancer. However, the anti-cancer effect of chelidonine, a major compound of C. majus extracts, on pancreatic cancer remains poorly understood. In this study, we found that treatment with chelidonine inhibited proliferation of BxPC-3 and MIA PaCa-2 human pancreatic cancer cells. Annexin-V/propidium iodide staining assay showed that this growth inhibitory effect of chelidonine was induced through apoptosis. We found that chelidonine treatment upregulated mRNA levels and transcription factor activity in both cell lines. Increases in protein expression levels of p53, GADD45A, p21 and cleaved caspase-3 were also observed, with more distinct changes in MIA PaCa-2 cells compared to the BxPC-3 cells. These results suggest that chelidonine induces pancreatic cancer apoptosis through the p53 and GADD45A pathways. Our findings provide new insights into the use of chelidonine for the treatment of pancreatic cancer.

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In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568210204916170096 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-11

Author(s):

P. Ulivi ◽

C. Arienti ◽

W. Zoli ◽

M. Scarsella ◽

S. Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Antitumor Efficacy ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

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Effect of Low Molecular Weight Heparins and Fondaparinux Upon Thrombin Generation Triggered by Human Pancreatic Cancer Cells BXPC3

Current Vascular Pharmacology ◽

10.2174/157016111206141210121441 ◽

2014 ◽

Vol 12 (6) ◽

pp. 893-902 ◽

Cited By ~ 5

Author(s):

Grigoris Gerotziafas ◽

Vassiliki Galea ◽

Elisabeth Mbemba ◽

Mouna Sassi ◽

Marie-Paule Roman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Weight ◽

Cancer Cells ◽

Thrombin Generation ◽

Human Pancreatic Cancer ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Pancreatic Cancer Cells

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Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽

10.3390/cancers13092017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2017

Author(s):

Lital Sharvit ◽

Rinat Bar-Shalom ◽

Naiel Azzam ◽

Yaniv Yechiel ◽

Solomon Wasser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Liquid ◽

Human Pancreatic Cancer ◽

P53 Signaling ◽

Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer

Cancers ◽

10.3390/cancers13020249 ◽

2021 ◽

Vol 13 (2) ◽

pp. 249

Author(s):

Ruediger Goess ◽

Ayse Ceren Mutgan ◽

Umut Çalışan ◽

Yusuf Ceyhun Erdoğan ◽

Lei Ren ◽

...

Keyword(s):

Diabetes Mellitus ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Islet Cells ◽

Human Pancreatic Cancer ◽

Type I ◽

Type Iv ◽

Pancreatic Cancer Cells

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

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HGF/c-Met Inhibition as Adjuvant Therapy Improves Outcomes in an Orthotopic Mouse Model of Pancreatic Cancer

Cancers ◽

10.3390/cancers13112763 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2763

Author(s):

Tony C. Y. Pang ◽

Zhihong Xu ◽

Alpha Raj Mekapogu ◽

Srinivasa Pothula ◽

Therese Becker ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Stellate Cell ◽

Smooth Muscle Actin ◽

Primary Tumour ◽

Human Pancreatic Cancer ◽

Pancreatic Stellate Cell ◽

Orthotopic Mouse Model ◽

Pancreatic Cancer Cells ◽

Angiogenic Effect

Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Methods: Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). Results: HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin−, CD45−), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. Conclusions: This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs.

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