Silencing of caveolin-1 in fibroblasts as opposed to epithelial tumor cells results in increased tumor growth rate and chemoresistance in a human pancreatic cancer model

Caveolin‑1 (Cav‑1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav‑1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav‑1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav‑1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well‑differentiated areas were characterized by a weak epithelial Cav‑1 expression. Cav‑1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav‑1 in fibroblasts resulted in a growth advantage and the chemoresistance of cancer cells when they were co‑injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav‑1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav‑1 in the stroma may represent a novel therapeutic approach in pancreatic cancer

New chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) as doxorubicin carriers

Since the late 1960s, the field of drug delivery has focused on the creation of new formulations with improved properties, taking much attention to drug release from the carrier. Liposomes and dendrimers represent two of the most studied drug carriers. A Modulatory Liposomal Controlled Release System (MLCRS) combining liposomal and dendrimeric technology has been recently published as well as Liposomal locked-in Dendrimers (LLDs) technology which was considered to be a class of MLCRSs. Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) can be defined as mixed nanosystems due to the combination of the bionanomaterials used and can offer advantages as drug carriers. This work deals with the production of two new chi-aDDnSs incorporating the newly synthesized dendrimer PG1. One of the two formulations bears the exact lipidic composition as the commercial liposomal drug " Myocet" Doxorubicin (Dox) was incorporated into conventional (free of dendrimer) liposomal formulations and into the corresponding chi-aDDnSs, and the physicochemical characteristics, the in vitro drug release and the in vitro cytotoxicity against human cancer cell lines were assessed. The results revealed a different modulation release effect of doxorubicin from the chi-aDDnS, compared to the Myocet replica. Pharmacological cytotoxicity concerning all the chi-aDDnSs was very close to that of the conventional liposomal systems. © 2010

Study of the relationship between sigma receptor expression levels and some common sigma ligand activity in cancer using human cancer cell lines of the nci-60 cell line panel

Sigma (σ) receptors have attracted great interest since they are implicated in various cellular functions and biological processes and diseases, including various types of cancer. The receptor family consists of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). Both σ receptor subtypes have been proposed as therapeutic targets for various types of cancers, and many studies have provided evidence that their selective ligands (agonists and antagonists) exhibit antiproliferative and cytotoxic activity. Still, the precise mechanism of action of both σ receptors and their ligands remains unclear and needs to be elucidated. In this study, we aimed to simultaneously determine the expression levels of both σ receptor subtypes in several human cancer cell lines. Additionally, we investigated the in vitro antiproliferative activity of some widely used σ1 and σ2 ligands against those cell lines to study the relationship between σ receptor expression levels and σ ligand activity. Finally, we ran the NCI60 COMPARE algorithm to further elucidate the cytotoxic mechanism of action of the selected σ ligands studied herein. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

In vitro activity of dietary flavonol congeners against human cancer cell lines

Flavonoids have physiological activity and a variety of pharmacological properties, including anticancer activity in vitro, but structure-anticancer activity relationships are unclear. The objectives of this work were to investigate the activity of dietary flavonol congeners against cell lines derived from human solid tumours and to examine whether the in vitro activity was associated with specific structural feature(s) of the molecules. Antiproliferative activity of the flavonol congeners was investigated against eight different human cancer cell lines representing different types of human solid tumour, using the sulforhodamine B (SRB) assay in accordance with the instructions published by the NCI. Cell cycle perturbations caused by the congeners were monitored by flow-cytometric analysis of DNA stained with propidium iodide. Most of the flavonols examined had weak antiproliferative and cytotoxic activity. Of all the flavonol congeners tested peracetylated tiliroside found to be the most powerful, with significant antiproliferative and cytotoxic activity. Most flavonols induced similar cell cycle perturbations, whereas induction of apoptosis was significant only for cells treated with peracetylated tiliroside. These findings indicated that the -OH groups of aromatic ring B were not linked to the cytotoxic and antiproliferative activity of the tested flavonols whereas peracetylation of the glycosides resulted in moderate improvement. In contrast, acetylation of tiliroside esterified with coumaric acid at position 5 of the sugar moiety greatly improved the activity of this congener. Overall, the results of this study suggest a critical role of sugar moiety substituents in the anticancer activity of the flavonols

In vitro activity of dietary flavonol congeners against human cancer cell lines

Background: Flavonoids have physiological activity and a variety of pharmacological properties, including anticancer activity in vitro, but structure-anticancer activity relationships are unclear. Aim: The objectives of this work were to investigate the activity of dietary flavonol congeners against cell lines derived from human solid tumours and to examine whether the in vitro activity was associated with specific structural feature(s) of the molecules. Methods: Antiproliferative activity of the flavonol congeners was investigated against eight different human cancer cell lines representing different types of human solid tumour, using the sulforhodamine B (SRB) assay in accordance with the instructions published by the NCI. Cell cycle perturbations caused by the congeners were monitored by flow-cytometric analysis of DNA stained with propidium iodide. Results: Most of the flavonols examined had weak antiproliferative and cytotoxic activity. Of all the flavonol congeners tested peracetylated tiliroside found to be the most powerful, with significant antiproliferative and cytotoxic activity. Most flavonols induced similar cell cycle perturbations, whereas induction of apoptosis was significant only for cells treated with peracetylated tiliroside. Conclusions: These findings indicated that the -OH groups of aromatic ring B were not linked to the cytotoxic and antiproliferative activity of the tested flavonols whereas peracetylation of the glycosides resulted in moderate improvement. In contrast, acetylation of tiliroside esterified with coumaric acid at position 5 of the sugar moiety greatly improved the activity of this congener. Overall, the results of this study suggest a critical role of sugar moiety substituents in the anticancer activity of the flavonols. © Springer-Verlag 2011

A new Chimeric Drug Delivery nano System (chi-aDDnS) composed of PAMAM G 3.5 dendrimer and liposomes as Doxorubicin's carrier. In vitro pharmacological studies

Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems due to the combination process of nanobiomaterials and can offer advantages as drug carriers. The role of the release modulator from the liposomal system is undertaken by the dendrimer molecules leading to new pharmacokinetic and, probably, pharmacological properties of the chimeric system. In this work, a conventional DOPC/DPPG liposomal system and a new chiaDDnS composed of liposomes (DOPC/DPPG) incorporating PAMAM G3,5 has been developed, Doxorubicin (Dox) was loaded in the systems and the final formulations were lyophilized. The physicochemical (spectroscopic and calorimetric) investigation concerning the chi-aDDnS, revealed a strong interaction between both lipophilic and hydrophilic parts of the liposomal membrane and the dendrimer, with the induction of multiple energetic states. These states are probably the basis of higher Dox encapsulation and slower release rate compared to the respective conventional liposome. These results, in conjunction with the increase in TI observed in two investigated cancer cell lines (i.e., MB231 and MCF7), compared to the respective conventional liposomal system and to the free Dox, make this new chi-aDDnS the basic candidate for further in vivo investigations. Copyright © 2011 American Scientific Publishers All rights reserved

A new chimeric drug delivery nano system (chi-aDDnS) composed of PAMAM G 3.5 dendrimer and liposomes as Doxorubicin\u2019s carrier. In vitro pharmacological studies

Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) could be defined as mixed nanosystems due to the combination process of nanobiomaterials and can offer advantages as drug carriers. The role of the release modulator from the liposomal system is undertaken by the dendrimer molecules leading to new pharmacokinetic and, probably, pharmacological properties of the chimeric system. In this work, a conventional DOPC/DPPG liposomal system and a new chiaDDnS composed of liposomes (DOPC/DPPG) incorporating PAMAM G3,5 has been developed, Doxorubicin (Dox) was loaded in the systems and the final formulations were lyophilized. The physicochemical (spectroscopic and calorimetric) investigation concerning the chi-aDDnS, revealed a strong interaction between both lipophilic and hydrophilic parts of the liposomal membrane and the dendrimer, with the induction of multiple energetic states. These states are probably the basis of higher Dox encapsulation and slower release rate compared to the respective conventional liposome. These results, in conjunction with the increase in TI observed in two investigated cancer cell lines (i.e., MB231 and MCF7), compared to the respective conventional liposomal system and to the free Dox, make this new chi-aDDnS the basic candidate for further in vivo investigations

Labd-14-ene-8,13-diol (sclareol) induces cell cycle arrest and apoptosis in human breast cancer cells and enhances the activity of anticancer drugs

Sclareol is a labdane-type diterpene that has demonstrated a significant cytotoxic activity against human leukemic cell lines. Here, we report the effect of sclareol against the human breast cancer cell lines MN1 and MDD2 derived from the parental cell line, MCF7. MN1 cells express functional p53, whereas MDD2 cells do not express p53. Flow cytometry analysis of the cell cycle indicated that sclareol was able to inhibit DNA synthesis induce arrest at the G0/1 phase of the cycle apoptosis independent of p53. Sclareol-induced apoptosis was further assessed by detection of fragmented DNA in the cells. Furthermore, sclareol enhanced the activity of known anticancer drugs, doxorubicin, etoposide and cisplatinum, against MDD2 breast cancer cell line. © 2006 Elsevier SAS. All rights reserved

The labdane diterpene sclareol (labd-14-ene-8, 13-diol) induces apoptosis in human tumor cell lines and suppression of tumor growth in vivo via a p53-independent mechanism of action

The labdane diterpene sclareol has demonstrated significant cytotoxicity against human tumor cell lines and human colon cancer xenografts. Therefore, there is need to elucidate the mode of action of this compound as very little information is known for the anticancer activity of sclareol and other labdane diterpenes, in general. COMPARE analysis of GI50 values for a number of human cancer cell lines was initially implicated in an effort to assign a putative mechanism of action to the compound. Sclareol-induced cell cycle arrest and apoptosis were assessed by flow cytometry and Western blot analyses. Finally, the anticancer ability of sclareol in vivo was assessed by using human colon cancer xenograft/mouse models. Sclareol arrested in vitro the growth of p53-deficient (HCT116p53-/-) human colon cancer cells and subsequently induced apoptosis by activating both caspases-8 and -9. Intraperitoneal administration of liposome-encapsulated sclareol at the maximum tolerated dose induced a marked growth suppression of HCT116p53-/- tumors established as xenografts in immunodeficient NOD/SCID mice. In conclusion, we demonstrate herein that sclareol kills human tumor cells by inducing arrest at the G1-phase of the cell cycle followed by apoptosis that involves activation of caspases-8, -9 and -3 via a p53-independent mechanism. These findings suggest that liposome-encapsulated sclareol possesses chemotherapeutic potential for the treatment of colorectal and other types of human cancer regardless of the p53-status. © 2011 Elsevier B.V