Aloe emodin: from anti- to pro-tumor action

Poor response of highly invasive forms of cancer to the treatment can be explained not only by the cell death resistant phenotype of low/undiff erentiated cell subpopulation but even more, by tumor repopulation as a reaction to damage triggered by the chemo- or radiotherapy. Regarding the serious limits of regular healing protocols, one of the pivotal challenges for biologists is to prove the relevance and discover the mechanisms behind traditional medicine-based tumor healing. One of the oldest and most powerful plants with 4000 years long tradition in folk medicine, Aloe vera is intensively studied during last century due to the treasure of active compounds with proven biological potential attractive not only for physicians and patients but also for scientists. Anthraquinones, emodin and aloe emodin (AE), derived from Aloe vera and diff erent plants from Polygonaceae family are defi nitely the most researched constituents. Aloe emodin owns multiple anti-tumor properties realized through induction of cell cycle arrest, cell death, diff erentiation and suppression of the malignant cell motility. However, its interaction with tumor cells is not unidirectional and due to the complex network of signals in the tumor microenvironment can be easily transformed from tumor destructive to tumor-stimulating. Therefore, this review will summarize direct tumoricidal eff ects as well as the interaction of AE with cells and mediators of the immune system. In addition, the potential of AE as chemo- or photosensitizer will be elaborated. Finally, new designs including chemical interventions on this molecule and nanotechnology will be discussed

Bipyraloxifene – a modified raloxifene vector against triple-negative breast cancer

Raloxifene, a selective oestrogen receptor modulator (SERM), has demonstrated efficacy in the prevention and therapy of oestrogen receptor-positive (ER+) breast cancer, with some degree of effectiveness against triple-negative forms. This suggests the presence of oestrogen receptor-independent pathways in raloxifene-mediated anticancer activity. To enhance the potential of raloxifene against the most aggressive breast cancer cells, hybrid molecules combining the drug with a metal chelator moiety have been developed. In this study, we synthetically modified the structure of raloxifene by incorporating a 2,2′-bipyridine (2,2′-bipy) moiety, resulting in [6-methoxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-[4-(2,2′-bipyridin-4′-yl-methoxy)phenyl]methanone (bipyraloxifene). We investigated the cytotoxic activity of both raloxifene and bipyraloxifene against ER+ breast adenocarcinomas, glioblastomas, and a triple-negative breast cancer (TNBC) cell line, elucidating their mode of action against TNBC. Bipyraloxifene maintained a mechanism based on caspase-mediated apoptosis but exhibited significantly higher activity and selectivity compared to the original drug, particularly evident in triple-negative stem-like MDA-MB-231 cells

Control of the of the final stage of immune-mediated diabetes by ISO-1, an antagonist of macrophage migration inhibitory factor

We recently showed that attenuation of inflammatory cytokine MIF with pharmacological inhibitor ISO-1 down-regulates the immune-mediated diabetes in mice. Here we explore the effects of MIF neutralization by ISO-1 on the local inflammatory pathway of the disease. In vivo treatment of mice with ISO-1 inhibited the expression of pro-inflammatory cytokines and iNOS in the pancreatic islets. Moreover, ISO-1 affected in vitro cytokine-induced NO pro­duction by fibroblasts, endothelial cells, insulinoma cells, and pancreatic islets, and rescued β cells from NO-dependent damage. These results suggest regulatory potential of ISO-1 at the level of the pancreas which can preserve the target tissue from autoimmune attack.Nedavno smo pokazali da neutralizacija inflamatornog citokina MIF-a farmakološkim inhibitorom ISO-1 negativno reguliše imunski posredovan dijabetes miševa. U ovom radu ispitivali smo efekte neutralizacije MIF-a pomoću ISO-1 na lokalne inflamatorne puteve bolesti. In vivo tretman miševa pomoću ISO-1 je inhibirao ekspresiju proinflamatornih citokina i inducibilne sintaze azot monoksida u ostrvcima pankreasa. Štaviše, ISO-1 je remetio in vitro produkciju azot monoksida indukovan u citokinima u fibroblastima, ćelijama endotela, insulinomama i pankreasnih ostrvaca i tako sačuvao beta ćelije od oštećenja izazvanih azot monoksidom. Ovi rezultati ukazuju na regulatorni potencijal ISO-1 na nivou ciljnog tkiva koji štiti ciljno tkivo od autoimunog ataka.Projekat ministarstva br. 143029

On the Discovery, Biological Effects, and Use of Cisplatin and Metallocenes in Anticancer Chemotherapy

The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity

Ti-SLActive and TiZr-SLActive Dental Implant Surfaces Promote Fast Osteoblast Differentiation

A primary goal in modern surface modification technology of dental implants is to achieve biocompatible surfaces with rapid but controlled healing which also allow health and longevity of implants. In order to realize all, understanding of osseointegration phenomena is crucial. Although Ti-SLA, Ti-SLActive and TiZr-SLActive surfaces have been successfully used in clinical implantology and were shown to notably reduce the primary healing time, available in vitro studies are sparse and do not concern or explore the mechanism(s) involved in human osteoblast behavior on these surfaces. Ti-SLA, Ti-SLActive, TiZr-SLActive, Ti cp, Ticer and Cercon surfaces were used. Osteoblast proliferation, cell cluster formation, morphological changes, induction of autophagy, nitric oxide (NO), reactive oxygen species/reactive nitrogen species (ROS/RNS) formation, osteocalcin (OC), bone sialoprotein (BSP) and collagen type I (Col-1) affected by various surfaces were analyzed. These surfaces induced formation of mature osteoblasts caused by elevated oxidative stress (ROS) followed by overexpression of osteoblast maturation key molecule (NO), with different intensity however. These mature osteoblasts induced upregulation of OC, BSP and Col-1, activating PI3/Akt signalling pathway resulting in autophagy, known as an important process in differentiation of osteoblast cells. Additional distinctive subpopulation identified on Ticer, Ti-SLA (after 5 days), Ti-SLActive and TiZr-SLActive surfaces (after 2 days) were forming cell clusters, essential for bone noduli formation and mineralisation. The results suggest that Ti- and TiZr-SLActive possess advanced properties in comparison with Ticer and Ti-SLA manifested as accelerated osteoblast differentiation. These effects could explain already known fast osseointegration of these surfaces in vivo

Effect of interleukin-17 on nitric oxide production in murine fibroblast-like cell line L929

The ability of interleukin-17 (IL-17) to induce nitric oxide (NO) synthesis in murine L929 fibroblasts was investigated. L929 cells were incubated with IL-17 and/or LPS, interferon-g (IFN-gama), interleukin-1 (IL-1), or dibutyryl-cAMP. NO production was assessed indirectly, by measuring nitrite accumulation in 24 h culture supernatants. L929 fibroblasts did not produce NO constitutively, nor IL-17 alone induced NO production. Of all other stimuli tested, only IFN-gama significantly up regulated nitrite level in L929 cell cultures. However, when IL-17 was applied simultaneously with each of the tested stimuli, NO synthesis was markedly elevated, thus indicating involvement of distinct signaling pathways of NO induction by IL-17 and other tested agents. Production of NO by IL-17+LPS-treated L929 cells was dependent on synthesis and activity of inducible NO synthase (iNOS), as indicated by abrogation of nitrite accumulation with protein synthesis inhibitor cycloheximide or selective inhibitor of iNOS, aminoguanidine. A role for protein tyrosine kinase (PTK) and transcription factor NF-kB in iNOS activation is suggested by reduction of NO synthesis with PTK inhibitor genistein and an inhibitor of NF-kB activation, pyrrolidine dithiocarbamate (PDTC). In contrast, protein kinase C inhibitor staurosporine was ineffective in blocking IL-17+LPS-induced NO production in L929 cells. Taken together, our results for the first time showed an active participation of IL-17 in co-induction of fibroblast NO synthesis with LPS, cytokines (IL-1, IFN-gama), or cAMP analogue, and suggested that IL-17 up-regulated NO synthesis in fibroblasts through mechanisms involving PTK and NF-kB activation.Ispitan je uticaj interleukina-17 (IL-17) na produkciju azot monoksida (NO) od strane L929 fibroblasta. L929 ćelije su inkubirane sa IL-17 i/ili LPS-om, interferonom-gama (IFN-gama), interleukinom-1 (IL-1), ili dibutiril-cAMP-om. Produkcija NO ispitana je indirektno, merenjem koncentracije nitrita akumuliranih nakon 24 h u supernatantu ćelijskih kultura. Kultivisani L929 fibroblasti nisu produkovali NO konstitutivno, niti je sam IL-17 indukovao NO produkciju. Od ostalih ispitanih agenasa samo je IFN-gama značajno povećao nivo nitrita u kulturama L929 ćelija. Međutim, kada je IL-17 primenjen sa bilo kojim od testiranih agenasa, došlo je do snažnog povećanja NO sinteze, što je ukazalo da su signalni putevi indukcije NO sa IL-17 i ostalim navedenim agensima različiti. Sprečavanje akumulacije nitrita inhibitorom proteinske sinteze cikloheksimidom ili selektivnim inhibitorom iNOS aminoguanidinom u ćelijama stimulisanim sa IL-17+LPS ukazalo je da NO produkcija zavisi od sinteze i aktivnosti enzima inducibilne NO sinteze (iNOS). Inhibitor protein tirozin kinaze (PTK), genistein i inhibitor aktivacije transkripcionog faktora NF-kB, pirolidin ditiokarbamat (PDTC), takođe su redukovali sintezu NO. Nasuprot tome, inhibitor protein kinaze C, staurosporin, nije blokirao NO produkciju L929 ćelija stimulisanih sa IL-17+LPS. U celini, naši rezultati su po prvi put pokazali aktivno učešće IL-17 u koindukciji NO sinteze sa LPS-om, citokinima (IL-1, IFN-gama), ili cAMP analogom u fibroblastima i ukazali da stimulacija NO sinteze sa IL-17 uključuje mehanizme zavisne od PTK i NF-kB.nul

Naturally occurring compounds in differentiation based therapy of cancer.

Differentiation of cancer cells entails the reversion of phenotype from malignant to the original. The conversion to cell type characteristic for another tissue is named transdifferentiation. Differentiation/transdifferentiation of malignant cells in high grade tumor mass could serve as a nonaggressive approach that potentially limits tumor progression and augments chemosensitivity. While this therapeutic strategy is already being used for treatment of hematological cancers, its feasibility for solid malignancies is still debated. We will presently discuss the natural compounds that show these properties, with focus on anthraquinones from Aloe vera, Senna, Rheum sp. and hop derived prenylflavonoids

Control of the of the final stage of immune-mediated diabetes by ISO-1, an antagonist of macrophage migration inhibitory factor

We recently showed that attenuation of inflammatory cytokine MIF with pharmacological inhibitor ISO-1 down-regulates the immune-mediated diabetes in mice. Here we explore the effects of MIF neutralization by ISO-1 on the local inflammatory pathway of the disease. In vivo treatment of mice with ISO-1 inhibited the expression of pro-inflammatory cytokines and iNOS in the pancreatic islets. Moreover, ISO-1 affected in vitro cytokine-induced NO pro­duction by fibroblasts, endothelial cells, insulinoma cells, and pancreatic islets, and rescued β cells from NO-dependent damage. These results suggest regulatory potential of ISO-1 at the level of the pancreas which can preserve the target tissue from autoimmune attack.Nedavno smo pokazali da neutralizacija inflamatornog citokina MIF-a farmakološkim inhibitorom ISO-1 negativno reguliše imunski posredovan dijabetes miševa. U ovom radu ispitivali smo efekte neutralizacije MIF-a pomoću ISO-1 na lokalne inflamatorne puteve bolesti. In vivo tretman miševa pomoću ISO-1 je inhibirao ekspresiju proinflamatornih citokina i inducibilne sintaze azot monoksida u ostrvcima pankreasa. Štaviše, ISO-1 je remetio in vitro produkciju azot monoksida indukovan u citokinima u fibroblastima, ćelijama endotela, insulinomama i pankreasnih ostrvaca i tako sačuvao beta ćelije od oštećenja izazvanih azot monoksidom. Ovi rezultati ukazuju na regulatorni potencijal ISO-1 na nivou ciljnog tkiva koji štiti ciljno tkivo od autoimunog ataka.Projekat ministarstva br. 143029

2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.

Investigations on the antitumor activity of metallacarboranes are sparse in the literature and limited to a handful of ruthena- and molybdacarboranes. In this study, the molybdacarborane fragment [3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] was combined with a vector molecule, inspired by the well-known drug tamoxifen or 4,4'-dihydroxytamoxifen (TAM-diOH). The molybdacarborane derivative [3,3-{4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine-κ2 N,N'}-3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] (10), as well as the ligand itself 4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (6) showed cytotoxic activities in the low micromolar range against breast adenocarcinoma (MDA-MB-231, MDA-MB-361 and MCF-7), human glioblastoma (LN-229) and human glioma (U-251) cell lines. In addition, compounds 6 and 10 were found to induce senescence and cytodestructive autophagy, lower ROS/RNS levels, but only the molybdacarborane 10 induced a strong increase of nitric oxide (NO) concentration in the MCF-7 cells

Potential of Tamoxifen-based Copper(II) Dichloride in Breast Cancer Therapy

Background: Estrogen receptor-posiƟ ve (ER+) breast cancer accounts for approximately 70% of all cases and, concordantly, anƟ -estrogen therapies present a leading therapeuƟ c choice. InteresƟ ngly, tamoxifen, which is the most commonly used drug, has also been proven eff ecƟ ve in hormone-independent forms of breast cancer, suggesƟ ng the existence of intracellular off -targets. Frequent acquisiƟ on of therapy resistance presents a plaƞ orm for the design of tamoxifen derivaƟ ves with a 2,2’-bipyridine unit enabling the coordinaƟ on of transiƟ on metal moieƟ es, such as copper(II) dichloride. Copper (Cu) is an essenƟ al element involved in the regulaƟ on of cellular growth and development. DisrupƟ on of its delicate homeostasis results in severe toxicity and hard medical condiƟ ons. Increased demand of cancer cells for this micronutrient makes it a valuable candidate for drug design in cancer treatment. The mechanism of acƟ on of Cu complexes is typically based on their ability to induce deadly oxidaƟ ve stress. This study evaluated the effi cacy of a copper–tamoxifen hybrid drug on a panel of breast cancer cell lines with varying receptor expression status. Material and Methods: The viability of breast adenocarcinoma cell lines MCF-7, MDA-MB-361, MDA-MB-231, 4T1 and glioma U251 was esƟ mated by MTT and CV assays. Flow cytometric analysis of cells stained with annexin V-FITC/propidium iodide, ApoStat, acridine orange, dihydrorhodamine 123 (DHR), dihydroethidium (DHE) or 4-amino-5-methylamino-2’,7’-difl uorofl uorescein diacetate (DAF) was used to evaluate cell death, caspase acƟ vity, autophagy, producƟ on of reacƟ ve oxygen and nitrogen species (ROS/RNS), respecƟ vely. Results: The Cu-tamoxifen hybrid drug displayed substanƟ ally higher hormone-receptor (HR) independent cytotoxic acƟ vity compared to previously reported metal complexes with a similar tamoxifen vector. Massive caspase-dependent apoptoƟ c cell death is parƟ ally aƩ enuated by an autophagic process that counteracts death signals. In contrast to the plaƟ num analogue, the copper-based tamoxifen derivaƟ ve reduces ROS/RNS that may be associated with the intracellular accumulaƟ on of the reduced form of CuI which is important for cuproptosis. Conclusion: This study demonstrates the potenƟ al of the copper–tamoxifen hybrid drug as an intriguing alternaƟ ve to commonly used plaƟ num complexes in treatment of cancer. Its safety and effi ciency will be further esƟ mated in vivoThe first number of Oncology Insights includes Proceedings book of The Sixth Congress of the Serbian Association for Cancer Research with international participation (Oct 2-4, 2023, Belgrade