scholarly journals The effect of hyperthermia (42°C) on the anti-tumoral effect of bromelain, N-acetyl cysteine, chemotherapeutic agents and their combinations - an in vitro evaluation

2018 ◽  
Author(s):  
Vanessa H.L. Wan ◽  
Krishna Pillai ◽  
Samina Badar ◽  
Javed Akhter ◽  
David L Morris
Keyword(s):  
Colony Formation ◽  
Cellular Proliferation ◽  
Single Agent ◽  
Cell Types ◽  
Chemotherapeutic Agents ◽  
Mucin Secretion ◽  
Development Of Resistance ◽  
Pancreatic Cancer Cells ◽  
Acetyl Cysteine

Bromelain, N-acetyl cysteine and their combinations show cytotoxicity at 37°C. Similarly, their combinations with common chemotherapeutic agents (gemcetabine, Mitomycin C, oxaliplatin and 5-FU) show enhanced cytotoxicity. Since, hyperthermia (42°C) inhibits cellular proliferation, we set out to determine if it would further enhance the effect of these agents. Tumour cells (pancreatic and colorectal) were grown in a 96 well plate and treated to various agents and their combinations at 37° and 42°C. The survival of cells at 72 hours was evaluated with sulfhordamine assay. Colony formation assay was performed to evaluate development of resistance to these agents and finally PAS staining was carried out to determine the effect of bromelain, Nacetylcysteine (NAC), oxaliplatin and their combinations on mucin secretion in ASPC-1 (pancreatic) cancer cells. Hyperthermia (42°C) enhanced cytotoxicity of certain agents or their combinations in some of the cell lines. It also showed the absence or a reduction of effect, with certain agents. Hyperthermia reduced colony formation in CFPAC cells and with agents (bromelain + NAC, gemcitabine, NAC + gemcitabine, Bromelain + NAC + Gemcitabine). A similar effect with 5FU, 5FU + NAC and 5FU + bromelain was observed. Hyperthermia reduced mucin secretion in ASPC-1 cells, with bromelain and its combinations with NAC and oxaliplatin. NAC as a single agent increased mucin with hyperthermia. The effect of hyperthermia on cytotoxicity of bromelain, NAC and their combinations with chemotherapeutic agents varied with agents, their combinations and cell types, showing an increase, null effect or a decrease. However, hyperthermia reduced colony formation and mucin secretion.

scholarly journals Selenium Induces Pancreatic Cancer Cell Death Alone and in Combination with Gemcitabine

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 149
Author(s):  
David J. Wooten ◽  
Indu Sinha ◽  
Raghu Sinha
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Single Agent ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Death ◽  
Pancreatic Cancer Cells

Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations’ (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.

scholarly journals Combination Delivery of Alpha-Tocopheryl Succinate and Curcumin Using a GSH-Sensitive Micelle (PAH-SS-PLGA) to Treat Pancreatic Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 778
Author(s):  
Tilahun Ayane Debele ◽  
Hung-Chang Wu ◽  
Shang-Rung Wu ◽  
Yan-Shen Shan ◽  
Wen-Pin Su
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Efficacy ◽  
Cellular Proliferation ◽  
Chemotherapeutic Agents ◽  
Proton Nuclear Magnetic Resonance ◽  
Chemical Structures ◽  
Pancreatic Cancer Cells ◽  
Tocopheryl Succinate ◽  
Combination Drugs

Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (1H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments.

scholarly journals Does Bromelain-Cisplatin Combination Afford In-Vitro Synergistic Anticancer Effects on Human Prostatic Carcinoma Cell Line, PC3?

2020 ◽  
Vol 9 ◽  
pp. 1749
Author(s):  
Fatemeh Amini Chermahini ◽  
Elham Raeisi ◽  
Mathias Hossain Aazami ◽  
Abbas Mirzaei ◽  
Esfandiar Heidarian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Viability ◽  
Cell Line ◽  
Colony Formation ◽  
Prostatic Carcinoma ◽  
Carcinoma Cell ◽  
Quantitative Polymerase Chain Reaction ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cell Line

Background: Bromelain enhances anticancer impacts to chemotherapeutic agents. The question as to whether bromelain does promote in-vitro cytotoxic and proapoptotic effects of cisplatin on human prostatic carcinoma PC3 cell line was investigated. Materials and Methods: PC3 (human prostatic carcinoma) cells were treated either single or in combination with bromelain and/or cisplatin. MTT, clonogenic assay, flow cytometry and real-time quantitative polymerase chain reaction were used to investigate cell viability, colony formation, proapoptotic potential and p53 gene expression, respectively. Results: Cisplatin (IC10) combined with bromelain (IC40) significantly affected PC3 cell viability, inhibited colony formation, as well increased p53 proapoptotic gene expression compared to cisplatin single treatment. Nevertheless, bromelain-cisplatin chemoherbal combination did not display any additive proapoptotic effect compared to single treatments. Conclusion: Bromelain-cisplatin chemoherbal combination demonstrated synergistic in-vitro anticancer effect on human prostatic carcinoma cell line, PC3, that drastically reduced required cisplatin dose. [GMJ.2020;9:e1749]

scholarly journals Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1284 ◽  
Author(s):  
Guerini ◽  
Triggiani ◽  
Maddalo ◽  
Bonù ◽  
Frassine ◽  
...  
Keyword(s):  
Current Literature ◽  
Single Agent ◽  
Drug Repurposing ◽  
Chemotherapeutic Agents ◽  
Metastatic Spread ◽  
Multi Drug Resistance ◽  
Wide Range ◽  
Disease Site

Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called “cancer stem cells”. Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.

scholarly journals MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

The BH3 Mimetic, ABT-737, Is Effective Against Bcl-2 Overexpressing Lymphoid Tumors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 826-826 ◽  
Author(s):  
Kylie D. Mason ◽  
Cassandra J. Vandenberg ◽  
Mark F. van Delft ◽  
Andrew H. Wei ◽  
Suzanne Cory ◽  
...  
Keyword(s):  
Cell Lines ◽  
Genetic Manipulation ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Clinical Samples ◽  
Bh3 Mimetic ◽  
Mouse Lymphoma

Abstract Lymphoid tumors often respond poorly to conventional cytotoxics, a common cause being their impaired sensitivity to apoptosis, such as that caused by Bcl-2 overexpression. A strategy to overcoming this is to use mimics of the natural antagonists of pro-survival Bcl-2, the BH3 only proteins. A promising BH3 mimetic is ABT-737, which targets Bcl-2 and closely related pro-survival proteins. We evaluated its potential utility by testing it on cell lines, clinical samples and on a relevant mouse lymphoma model. We assessed the sensitivity of B cell lymphoma cell lines and primary CLL samples to ABT-737, either alone or in combination. To ascertain its efficacy in vivo, we utilized a mouse model based on the Eμ-myc tumor that is readily transplantable and amenable to genetic manipulation. When syngeneic recipient mice were inoculated with tumors, they develop widespread lymphoma, fatal unless treated by agents such as cyclophosphamide. We found that ABT-737, on its own, was cytotoxic only to a subset of cell lines and primary CLL samples. However, it can synergize potently with agents such as dexamethasone, suggesting that this agent might be useful in combination with currently used chemotherapeutics. In the Eμ myc mouse lymphoma model, treatment with ABT-737 alone did not control the disease as multiple independently derived tumors proved refractory to treatment with this agent. However, ABT-737 was partially effective as a single agent for treating bitransgenic tumors derived from crosses of the Eμmyc and Eμ-bcl-2 transgenic mice. ABT-737 therapy prolonged the survival of recipient mice transplanted with tumors from 30 to 60 days. When combined with a low dose of cyclophosphamide (50mg/kg), long term stable remissions were achieved, which were sustained even longer than control mice treated with much higher doses of cyclophosphamide (300mg/kg). We found that ABT-737 was well tolerated as a single agent and when combined with low doses of cytotoxics such as cyclophosphamide. Thus, ABT-737 may prove to be efficacious for those tumors highly dependent on Bcl-2 for their survival. We found that despite its high affinity for Bcl-2, Bcl-xL and Bcl-w, many cell types proved refractory to ABT-737 as a single agent. We show that this resistance reflects its inability to target another pro-survival relative Mcl-1. Down-regulation of Mcl-1 by several strategies conferred sensitivity to ABT-737. Furthermore, enforced Mcl-1 expression in the Eμmyc/bcl-2 bitransgenic mouse lymphoma model conferred marked resistance as mice transplanted with such tumors died as rapidly as the untreated counterparts. However, enhanced Bcl-2 overexpression on these tumors had little impact on the in vivo response, suggesting that ABT-737 can be utilized even when Bcl-2 is markedly overexpressed. ABT-737 appears to be a promising agent for the clinic. It potently sensitizes certain lymphoid tumors to conventional cytotxics in vitro. The synergy observed between dexamethasone and ABT-737 on some lymphoid lines in culture suggests that it is attractive for clinical testing. Encouragingly, ABT-737 appeared efficacious in vivo against Bcl-2 overexpressing tumors when combined with a reduced dose of cyclophosphamide, suggesting that it will be useful for treating even those Bcl-2-overexpressing tumors that are normally highly chemoresistant.

In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5503-5503
Author(s):  
W. K. Huh ◽  
J. M. Straughn ◽  
D. E. Cohn
Keyword(s):  
Endometrial Cancer ◽  
Single Agent ◽  
Response Rates ◽  
Chemotherapeutic Agents ◽  
Primary Objective ◽  
Stage I ◽  
Chemotherapy Response ◽  
Vitro Assay ◽  
Significant Difference

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]

Targeting the Rho-ROCK pathway to treat pancreatic cancer: The use of unique preclinical models to ascertain the effects on cancer growth and metastasis.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 312-312
Author(s):  
Venessa T. Chin ◽  
James Conway ◽  
Adnan Nagrial ◽  
Lorraine A. Chantrill ◽  
Angela Chou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Colony Formation ◽  
Differential Effect ◽  
Cellular Proliferation ◽  
Small Gtpase ◽  
Model Systems ◽  
Imaging Results ◽  
Rock Inhibition

312 Background: Pancreatic cancer (PC) is a highly lethal and genetically heterogenous disease. Genomic sequence data from the Australian Pancreatic Cancer Genome Initiative (APGI) has identified a subset of patients with ROCK-1 amplification. ROCK-1 is a downstream target of Rho, a small GTPase that plays an important role in regulating proliferation, invasion and metastasis of cancer cells. Our aim was to analyse the effects of inhibiting ROCK-1 using specific small molecule inhibitors (Fasudil and Y-27632) in well annotated and robust pre-clinical model systems generated as part of our APGI efforts. Methods: Patient derived cell lines (PDCL) and xenografts (PDX) were used to test the effectiveness of ROCK-1 inhibitors (RI). Colony formation and 3-D organotypic assays tested cellular proliferation and invasion. In vivo, pre-clinical trials assessed the effect gemcitabine (G) +/- RI on a range of PDXs with varying tumour ROCK expression, including one G resistant model. A PDCL shown to form metastases when injected orthotopically into mice has been labeled with firefly luciferase. The effect of RI on metastasis formation will be assessed in vivo using real time imaging. Results: ROCK inhibition has a differential effect on colony formation on PDCLs in vitro, and inhibits cellular invasion. A statistically significant increase in median survival in the G + RI group compared with G alone, was seen in 3 PDXs, including the G resistant tumour. 1 PDX showed a decrease in tumour size at 200 days in the G + RI group. Conclusions: ROCK inhibition has a differential effect in vitro, but an anti-tumour effect in vivo, including overcoming resistance to G. This suggests that effects on the tumour micro-environment are an important mechanism of action. RI have the potential to be an effective therapy in PC.

scholarly journals A Tetravalent Biparatopic Antibody Causes Strong HER2 Internalization and Inhibits Cellular Proliferation

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1157
Author(s):  
Filippo Benedetti ◽  
Katharina Stadlbauer ◽  
Gerhard Stadlmayr ◽  
Florian Rüker ◽  
Gordana Wozniak-Knopp
Keyword(s):  
Cell Line ◽  
Cellular Proliferation ◽  
Treatment Options ◽  
Single Agent ◽  
Her2 Positive ◽  
Proliferative Effect ◽  
Efficient Reduction ◽  
Anti Cancer ◽  
Suitable Target

The overexpression of tyrosine kinase HER2 in numerous cancers, connected with fierce signaling and uncontrolled proliferation, makes it a suitable target for immunotherapy. The acquisition of resistance to currently used compounds and the multiplicity of signaling pathways involved prompted research into the discovery of novel binders as well as treatment options with multiple targeting and multispecific agents. Here we constructed an anti-HER2 tetravalent and biparatopic symmetrical IgG-like molecule by combining the Fab of pertuzumab with a HER2-specific Fcab (Fc fragment with antigen binding), which recognizes an epitope overlapping with trastuzumab. In the strongly HER2-positive cell line SK-BR-3, the molecule induced a rapid and efficient reduction in surface HER2 levels. A potent anti-proliferative effect, specific for the HER2-positive cell line, was observed in vitro, following the induction of apoptosis, and this could not be achieved with treatment with the mixture of pertuzumab and the parental Fcab. The inhibitory cytotoxic effect of our antibody as a single agent makes it a promising contribution to the armory of anti-cancer molecules directed against HER2-addicted cells.

scholarly journals Expression of c-myb and B-myb, but not A-myb, correlates with proliferation in human hematopoietic cells

Blood ◽  
1991 ◽  
Vol 77 (1) ◽  
pp. 149-158 ◽  
Author(s):  
J Golay ◽  
A Capucci ◽  
M Arsura ◽  
M Castellano ◽  
V Rizzo ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Cellular Proliferation ◽  
Cell Types ◽  
T And B Lymphocytes ◽  
Thymidine Uptake ◽  
Mitogenic Stimulation ◽  
Myb Gene ◽  
Normal Human

Abstract The steady-state expression of three members of the myb family of genes, c-myb, B-myb, and A-myb, was studied in four purified normal human hematopoietic cell types, ie, T and B lymphocytes, monocytes, and granulocytes. The c-myb proto-oncogene is low to undetectable in resting T and B lymphocytes and shows a biphasic induction in both cell types after mitogenic stimulation, with a first peak at 3 hours and a second and stronger induction at 44 to 72 hours. Study of the B-myb gene showed that this gene is low to undetectable in resting T or B cells and is strongly induced after mitogenic stimulation with a peak between 44 and 72 hours in both cell types. Finally, the A-myb gene shows a pattern of expression in lymphocytes different from that of c- myb and B-myb. It is expressed in resting T lymphocytes and its levels gradually decrease after mitogenic stimulation to become undetectable at 48 hours. It is also expressed in a subpopulation of large B lymphocytes but not in in vitro activated B cells. Neither of the three members of the myb family of genes was expressed in monocytes and granulocytes, even after functional activation of these cells. Taken together, these data bring further evidence for the role of c-myb in cellular proliferation and on the basis of the kinetics of its induction relative to thymidine uptake, we hypothesize that it may have a role during G1 progression in addition to that already documented for entry into S phase. Furthermore, our studies indicate that another member of the myb family of genes, B-myb, may also be involved in cellular proliferation, because its expression correlates with the induction of mitogenesis.

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