Frondoside A suppressive effects on lung cancer survival, tumor growth, angiogenesis, invasion, and metastasis

A major challenge for oncologists and pharmacologists is to develop less toxic drugs that will improve the survival of lung cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa and was shown to be a highly safe compound. We investigated the impact of Frondoside A on survival, migration and invasion in vitro, and on tumor growth, metastasis and angiogenesis in vivo alone and in combination with cisplatin. Frondoside A caused concentration-dependent reduction in viability of LNM35, A549, NCI-H460-Luc2, MDA-MB-435, MCF-7, and HepG2 over 24 hours through a caspase 3/7-dependent cell death pathway. The IC50 concentrations (producing half-maximal inhibition) at 24 h were between 1.7 and 2.5 mu M of Frondoside A. In addition, Frondoside A induced a time- and concentration-dependent inhibition of cell migration, invasion and angiogenesis in vitro. Frondoside A (0.01 and 1 mg/kg/day i.p. for 25 days) significantly decreased the growth, the angiogenesis and lymph node metastasis of LNM35 tumor xenografts in athymic mice, without obvious toxic side-effects. Frondoside A (0.1-0.5 mu M) also significantly prevented basal and bFGF induced angiogenesis in the CAM angiogenesis assay. Moreover, Frondoside A enhanced the inhibition of lung tumor growth induced by the chemotherapeutic agent cisplatin. These findings identify Frondoside A as a promising novel therapeutic agent for lung cancer

Purification, Conformational Analysis and Cytotoxic Activities of Host-Defense Peptides from the Giant Gladiator Treefrog Boana boans (Hylidae: Hylinae)

International audienceFrogs from the extensive amphibian family Hylidae are a rich source of peptides with therapeutic potential. Peptidomic analysis of norepinephrine-stimulated skin secretions from the Giant Gladiator Treefrog Boana boans (Hylidae: Hylinae) collected in Trinidad led to the isolation and structural characterization of five host-defense peptides with limited structural similarity to figainin 2 and picturin peptides from other frog species belonging to the genus Boana. In addition, the skin secretions contained high concentrations of tryptophyllin-BN (WRPFPFL) in both C-terminally α-amidated and non-amidated forms. Figainin 2BN (FLGVALKLGKVLG KALLPLASSLLHSQ) and picturin 1BN (GIFKDTLKKVVAAVLTTVADNIHPK) adopt α-helical conformations in trifluroethanol–water mixtures and in the presence of cell membrane models (sodium dodecylsulfate and dodecylphosphocholine micelles). The CD data also indicate contributions from turn structures. Both peptides and picturin 2BN (GLMDMLKKVGKVALT VAKSALLP) inhibited the growth of clinically relevant Gram-negative and Gram-positive bacteria with MIC values in the range 7.8–62.5 µM. Figainin 2BN was potently cytotoxic to A549, MDA-MB-231 and HT-29 human tumor-derived cells (LC50 = 7–14 µM) but displayed comparable potency against non-neoplastic HUVEC cells (LC50 = 15 µM) indicative of lack of selectivity for cancer cells

Antimicrobial, cytotoxic and insulin‐releasing activities of the amphibian host‐defense peptide ocellatin‐3N and its L‐lysine‐substituted analogs

The host-defense peptide ocellatin-3N (GIFDVLKNLAKGVITSLAS.NH2), first isolated from the Caribbean frog Leptodactylus nesiotus, inhibited growth of clinically relevant Gram-positive and Gram-negative bacteria as well as a strain of the major emerging yeast pathogen Candida parapsilosis. Increasing cationicity while maintaining amphipathicity by the substitution Asp(4)-> Lys increased potency against the microorganisms by between 4- and 16-fold (MIC <= 3 mu M) compared with the naturally occurring peptide. The substitution Ala(18)-> Lys and the double substitution Asp(4)-> Lys and Ala(18)-> Lys had less effects on potency. The [D4K] analog also showed 2.5- to 4-fold greater cytotoxic potency against non-small-cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells (LC50 values in the range of 12-20 mu M) compared with ocellatin-3N but was less hemolytic to mouse erythrocytes. However, the peptide showed no selectivity for tumor-derived cells [LC50 = 20 mu M for human umbilical vein endothelial cells (HUVECs)]. Ocellatin-3N and [D4K]ocellatin-3N stimulated the release of insulin from BRIN-BD11 clonal beta-cells at concentrations >= 1 nM, and [A18K]ocellatin-3N, at concentrations >= 0.1 nM. No peptide stimulated the release of lactate dehydrogenase at concentrations up to 3 mu M, indicating that plasma membrane integrity had been preserved. The three peptides produced an increase in intracellular [Ca2+] in BRIN-BD11 cells when incubated at a concentration of 1 mu M. In view of its high insulinotropic potency and relatively low hemolytic activity, the [A18K] ocellatin analog may represent a template for the design of agents with therapeutic potential for the treatment of patients with type 2 diabetes

Rhus coriaria suppresses angiogenesis, metastasis and tumor growth of breast cancer through inhibition of STAT3, NFκB and nitric oxide pathways

Recently, we reported that Rhus coriaria exhibits anticancer activities by promoting cell cycle arrest and autophagic cell death of the metastatic triple negative MDA-MB-231 breast cancer cells. Here, we investigated the effect of Rhus coriaria on the migration, invasion, metastasis and tumor growth of TNBC cells. Our current study revealed that non-cytotoxic concentrations of Rhus coriaria significantly inhibited migration and invasion, blocked adhesion to fibronectin and downregulated MMP-9 and prostaglandin E2 (PgE2). Not only did Rhus coriaria decrease their adhesion to HUVECs and to lung microvascular endothelial (HMVEC-L) cells, but it also inhibited the transendothelial migration of MDA-MB-231 cells through TNF-α-activated HUVECs. Furthermore, we found that Rhus coriaria inhibited angiogenesis, reduced VEGF production in both MDA-MB-231 and HUVECs and downregulated the inflammatory cytokines TNF-α, IL-6 and IL-8. The underlying mechanism for Rhus coriaria effects appears to be through inhibiting NFκB, STAT3 and nitric oxide (NO) pathways. Most importantly, by using chick embryo tumor growth assay, we showed that Rhus coriaria suppressed tumor growth and metastasis in vivo. The results described in the present study identify Rhus coriaria as a promising chemopreventive and therapeutic candidate that modulate triple negative breast cancer growth and metastasis.UAEU Program for Advanced Research (Grant 31S111-UPAR), the Zayed Center for Health Sciences (ZCHS) research grant (grant 31R021) and the Terry Fox Foundation Grant (2013) to Rabah Iratni

SMARCAD1 in Breast Cancer Progression

Background/Aims: Breast cancer is the most common cancer in women worldwide, and within this cancer type, triple-negative breast cancers have the worst prognosis. The identification of new genes associated with triple-negative breast cancer progression is crucial for developing more specific anti-cancer targeted therapies, which could lead to a better management of these patients. In this context, we have recently demonstrated that SMARCAD1, a DEAD/H box-containing helicase, is involved in breast cancer cell migration, invasion, and metastasis. The aim of this study was to investigate the impact of the stable knockdown of SMARCAD1 on human breast cancer cell progression. Methods: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of the stable knockdown of SMARCAD1 on human breast cancer cell proliferation and colony growth in vitro and on tumour growth in chick embryo and nude mouse xenograft models in vivo using MDA-MB-231 (ER-/PR-/ HER2-) and T47D (ER+/PR+/-/HER2-) human breast cancer cell lines. Results: We found that SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKβ expression. Conclusion: These results indicate that SMARCAD1 is involved in breast cancer progression and can be a promising target for breast cancer therapy

Synthesis of New Chromene Derivatives Targeting Triple-Negative Breast Cancer Cells

Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives (C1 and C2) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in β-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC.Scopu

Exploring the Anticancer Potential of <i>Origanum majorana</i> Essential Oil Monoterpenes Alone and in Combination against Non-Small Cell Lung Cancer

Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate worldwide despite the remarkable advances in its treatment. Origanum majorana Essential Oil (OMEO) has been shown to be effective against non-small cell lung cancer (NSCLC) cells, decreasing their viability and colony growth in vitro, as well as inhibiting tumor growth in chick embryo chorioallantoic membranes (CAM) and nude mice in vivo. OMEO is mainly composed of four monoterpenes, namely terpinen-4-ol, sabinene hydrate, α-terpinene, and γ-terpinene. In this study, we aimed to investigate the potential anticancer effects of these monoterpenes, either alone or in combination, on NSCLC. Our findings indicate that these four monoterpenes significantly decreased NSCLC cell viability in a concentration-dependent manner, reduced their colony growth in vitro, and also downregulated survivin expression in these cells. Moreover, different combined mixtures of these monoterpenes further enhanced their anticancer effects on cellular viability, with a terpinen-4-ol and sabinene hydrate combination being the most potent. We also found that terpinen-4-ol, in combination with sabinene hydrate, markedly enhanced the anticancer effect of the individual monoterpenes on NSCLC viability within a shorter treatment duration through, at least in part, survivin downregulation. Furthermore, this combination enhanced the inhibition of colony growth in vitro and the tumor growth of NSCLC cells xenografted onto chick embryo CAM in vivo. Altogether, our study highlights the potential of these monoterpenes for use in further pre-clinical investigations against various cancer hallmarks

Frondoside A Enhances the Anti-Cancer Effects of Oxaliplatin and 5-Fluorouracil on Colon Cancer Cells

Over recent years, we have demonstrated that Frondoside A, a triterpenoid glycoside isolated from an Atlantic sea cucumber, has potent in vitro and in vivo anti-cancer effects against human pancreatic, breast, and lung cancer. We have also demonstrated that Frondoside A is able to potentiate and/or synergize the anti-cancer effects of major classical cytotoxic agents, namely, gemcitabine, paclitaxel, and cisplatin, in the treatment of pancreatic, breast, and lung cancer, respectively. This study evaluates the impact of Frondoside A alone and in combination with the standard cytotoxic drugs oxaliplatin and 5-fluorouracil (5-FU) in the treatment of colon cancer using three human colon cancer cell lines, namely, HT-29, HCT-116, and HCT8/S11. We demonstrate that Frondoside A, oxaliplatin, and 5-FU cause a concentration- and time-dependent reduction in the number of HT-29 colon cancer cells. A concentration of 2.5 &micro;M of Frondoside A led to almost 100% inhibition of cell numbers at 72 h. A similar effect was only observed with a much higher concentration (100 &micro;M) of oxaliplatin or 5-FU. The reduction in cell numbers by Frondoside A, oxaliplatin, and 5-FU was also confirmed in two other colon cancer cell lines, namely, HCT8/S11 and HCT-116, treated for 48 h. The combinations of low concentrations of these drugs for 48 h in vitro clearly demonstrated that Frondoside A enhances the inhibition of cell numbers induced by oxaliplatin or 5-FU. Similarly, such a combination also efficiently inhibited colony growth in vitro. Interestingly, we found that the inhibition of ERK1/2 phosphorylation was significantly enhanced when Frondoside A was used in combination treatments. Moreover, we show that Frondoside A and 5-FU, when used alone, induce a concentration-dependent induction of apoptosis and that their pro-apoptotic effect is dramatically enhanced when used in combination. We further demonstrate that apoptosis induction upon the treatment of colon cancer cells was at least in part a result of the inhibition of phosphorylation of the survival kinase AKT, leading to caspase-3 activation, poly (ADP-ribose) polymerase (PARP) inactivation, and consequently DNA damage, as suggested by the increase in the level of &gamma;H2AX. In light of these findings, we strongly suggest that Frondoside A may have a role in colon cancer therapy when used in combination with the standard cytotoxic drugs oxaliplatin and 5-FU

Akt2 knock-down reveals its contribution to human lung cancer cell proliferation, growth, motility, invasion and endothelial cell tube formation

International audienceThe Akt/PKB serine/threonine protein kinase consists of three isoforms: Akt-1, −2 and −3. Their overexpression has been detected in human cancers, but their roles in cancer progression are unclear. We investigated the impact of specific silencing of Akt1 and Akt2 on human lung cancer cell proliferation, colony growth, motility, and invasion in vitro as well as tumor growth in vivo using human Non-Small Cell Lung Cancer cells LNM35, and on the vascular tube formation using HUVEC cells. Although silencing of Akt1 decreased cellular invasion at least in part via COX-2 inhibition, it had almost no effect on cell motility, proliferation, colony formation, and angiogenesis. Transient as well as stable silencing of Akt2 resulted in a strong inhibition of Rb phosphorylation associated with a decrease in cellular proliferation and colony formation, leading to the inhibition of tumor growth in the xenograft model. Silencing of Akt2 also reduced cellular motility and invasion in vitro, presumably via COX-2 inhibition. Moreover, silencing of Akt2 in the HUVEC cells resulted in the inhibition of their spontaneous angiogenic phenotype. Altogether, these results indicate that Akt2 plays an important role in lung cancer progression and can be a promising target for lung cancer therapy