In Vitro Cytotoxic Activity of African Plants: A Review

In African countries, cancer not only is a growing problem, but also a challenge because available funding and resources are limited. Therefore, African medicinal plants play a significant role in folk medicine and some of them are traditionally used for the treatment of cancer. The high mortality rate and adverse effects associated with cancer treatments have encouraged the search for novel plant-based drugs, thus, some African plants have been studied in recent years as a source of molecules with proven cytotoxicity. This review aims to discuss the cytotoxic activity, in vitro, of African plant crude extracts against cancer cell lines. For the period covered by this review (2017–2021) twenty-three articles were found and analyzed, which included a total of 105 plants, where the main cell lines used were those of breast cancer (MCF-7 and MDA-MBA-231) and colorectal cancer (HCT-116 and Caco-2), which are among the most prevalent cancers in Africa. In these studies, the plant crude extracts were obtained using different solvents, such as ethanol, methanol, or water, with variable results and IC₅₀ values ranging from <20 µg/mL to >200 µg/mL. Water is the preferred solvent for most healers in African countries, however, in some studies, the aqueous extracts were the least potent. Apoptosis and the induction of cell cycle arrest may explain the cytotoxic activity seen in many of the plant extracts studied. Considering that the criteria of cytotoxicity activity for the crude extracts, as established by the American National Cancer Institute (NCI), is an IC₅₀ < 30 μg/mL, we conclude that many extracts from the African flora could be a promising source of cytotoxic agents.     

Structure–Activity Relationship of the Thiacalix[4]arenes Family with Sulfobetaine Fragments: Self-Assembly and Cytotoxic Effect against Cancer Cell Lines

Regulating the structure of macrocyclic host molecules and supramolecular assemblies is crucial because the structure–activity relationship often plays a role in governing the properties of these systems. Herein, we propose and develop an approach to the synthesis of the family of sulfobetaine functionalized thiacalix[4]arenes with regulation of the self-assembly and cytotoxic effect against cancer cell lines. The dynamic light scattering method showed that the synthesized macrocycles in cone, partial cone and 1,3-alternate conformations form submicron-sized particles with Ag⁺ in water, but the particle size and polydispersity of the systems studied depend on the macrocycle conformation. Based on the results obtained by ¹H and ¹H-¹H NOESY NMR spectroscopy and transmission electron microscopy for the macrocycles and their aggregates with Ag⁺, a coordination scheme for the Ag⁺ and different conformations of p-tert-butylthiacalix[4]arene functionalized with sulfobetaine fragments was proposed. The type of coordination determines the different shapes of the associates. Cytotoxic properties are shown to be controlled by the shape of associates, with the highest activity demonstrated by thiacalix[4]arenes in partial cone conformation. This complex partial cone/Ag⁺ is two times higher than the reference drug imatinib mesylate. High selectivity against cervical carcinoma cell line indicates the prospect of their using as components of new anticancer system.     

Medicinal Plants Used for Anxiety,Depression, or Stress Treatment: An Update

Depression, anxiety, stress, and other mental disorders, which are on the rise worldwide, are indications that pharmacological therapy can have serious adverse effects, which is why many patients prefer to use herbal products to treat these symptoms. Here, we reviewed plants and products derived from them that are commonly used for the above indications, focusing on clinical data and safety profiles. While lavender, hops, maypop, lemon balm, and valerian have consistently been shown in clinical trials to relieve mild forms of neurological disorders, particularly depression, anxiety, and stress, currently available data do not fully support the use of peppermint for anxiety disorders and depression. Recent studies support the use of saffron for depression; however, its toxicological profile raises safety concerns. St. John’s wort is effective in alleviating mild to moderate depression; however, careful use is necessary particularly due to possible interactions with other drugs. In conclusion, more studies are needed to validate the mechanism of action so that these plants can be used successfully and safely to alleviate or eliminate various mental disorders.     

Evaluation of In Vitro Cytotoxic Potential of Avarol towards Human Cancer Cell Lines and In Vivo Antitumor Activity in Solid Tumor Models

The goal of this study was to determine the activity in vitro and in vivo of avarol, a sesquiterpene hydroquinone originating from the Dysidea avara sponge from the south Adriatic Sea, against different cancer cell lines and two types of mouse carcinoma. To investigate the in vitro cytotoxicity, a human cervix adenocarcinoma cell line (HeLa), human colon adenocarcinoma (LS174), human non-small-cell lung carcinoma (A549), and a normal human fetal lung fibroblast cell line (MRC-5) were used. The in vivo antitumor activity was investigated against two transplantable mouse tumors, the Ehrlich carcinoma (EC) and cervical cancer (CC-5). The effect of avarol on cancer cell survival, which was determined by the microculture tetrazolium test, confirmed a significant in vitro potency of avarol against the investigated cell lines, without selectivity towards MRC-5. The highest cytotoxicity was exhibited against HeLa cancer cells (10.22 ± 0.28 μg/mL). Moreover, potent antitumor activity against two tumor models was determined, as the intraperitoneal administration of avarol at a dose of 50 mg/kg resulted in a significant inhibition of tumor growth in mice. After three administrations of avarol, a 29% inhibition of the EC growth was achieved, while in the case of CC-5, a 36% inhibition of the tumor growth was achieved after the second administration of avarol. Therefore, the results indicate that this marine sesquiterpenoid hydroquinone could be a promising bioactive compound in the development of new anticancer medicine.     

5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT,and ERK Activity

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.     

Selective Apoptotic Effect of Plasma Activated Liquids on Human Cancer Cell Lines

Plasma medicine is a new field focusing on biomedical and clinical applications of cold gas plasmas, including their anticancer effects. Cold plasmas can be applied directly or indirectly as plasma-activated liquids (PAL). The effects of plasma-activated cell growth medium (PAM) and plasma-activated phosphate buffered saline (PAPBS) were tested, using a plasma pen generating streamer corona discharge in ambient air, on different cancer cell lines (melanoma A375, glioblastoma LN229 and pancreatic cancer MiaPaCa-2) and normal cells (human dermal fibroblasts HDFa). The viability reduction and apoptosis induction were detected in all cancer cells after incubation in PAL. In melanoma cells we focused on detailed insights to the apoptotic pathways. The anticancer effects depend on the plasma treatment time or PAL concentration. The first 30 min of incubation in PAL were enough to start processes leading to cell death. In fibroblasts, no apoptosis induction was observed, and only PAPBS, activated for a longer time, slightly decreased their viability. Effects of PAM and PAPBS on cancer cells showed selectivity compared to normal fibroblasts, depending on correctly chosen activation time and PAL concentration, which is very promising for potential clinical applications. This selectivity effect of PAL is conceivably induced by plasma-generated hydrogen peroxide.     

Plants Used for the Traditional Management of Cancer in the Eastern Cape Province of South Africa: A Review of Ethnobotanical Surveys,Ethnopharmacological Studies and Active Phytochemicals

Cancer occurrence is rapidly increasing all over the world, including in developing countries. The current trend in cancer management requires the use of herbal remedies since the majority of anticancer drugs are known to be costly, with unwanted side effects. In the Eastern Cape province, the use of medicinal plants for cancer management has been climbing steadily over the past two decades due to their cultural belief, low cost, efficacy, and safety claims. With the aim of identifying some potential anticancer plants for probable drug development, this study was undertaken to review plants reported by ethnobotanical surveys in the Eastern Cape province of South Africa for the traditional management of cancer. Information regarding plants used for cancer management in the Eastern Cape province was obtained from multidisciplinary databases and ethnobotanical books. About 24 plant species belonging to twenty families have been reported to be used for the traditional management of cancer in the Eastern Cape province. Among the anticancer plant species, only 16 species have been explored scientifically for their anticancer activities. This review authenticated the use of anticancer plant species in the Eastern Cape province and, therefore, identified several promising unexplored species for further scientific evaluation.     

Systematic Study on the Cytotoxic Potency of Commonly Used Dimeric Metal Precursors in Human Cancer Cell Lines

The cytotoxicities of seven dimeric metal species of the general formula [M(arene)Cl₂]₂, commonly used as precursors for complex synthesis and deemed biologically inactive, are investigated in seven commonly employed human cancer cell lines. Four of these complexes featured a ruthenium(II) core, where p-cymene, toluene, benzene and indane were used as arenes. Furthermore, the osmium(II) p-cymene dimer, as well as the Cp* dimers of rhodium(III) and its heavier analogue iridium(III) were included in this work (Cp*=1,2,3,4,5-pentamethylcyclopentadienide). While the cytotoxic potencies of the ruthenium(II) and osmium(II) dimers are very low (or not even detectable at applicable concentrations), surprising activity, especially in cells from ovarian malignancies (with one or two-digit micromolar IC₅₀ values), have been found for the rhodium(III) and iridium(III) representatives. This publication is aimed at all researchers using synthetic procedures based on functionalization of these dimeric starting materials to rationalize changes in biological properties, especially cytotoxicity in cancer cells.     

A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics

Homeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtual screening study is presented to filter novel strong CCR7 binding phytochemicals from Saudi medicinal plants that have a higher binding affinity for the intracellular allosteric binding pocket. By doing so, three small natural molecules named as Hit-1 (1,8,10-trihydroxy-3-methoxy-6-methylanthracen-9(4H)-one), Hit-2 (4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one), and Hit-3 (10-methyl-12,13-dihydro-[1,2]dioxolo[3,4,5-de]furo[3,2-g]isochromeno[4,3-b]chromen-8-ol) are predicted showing strong binding potential for the CC chemokine receptor 7 allosteric pocket. During molecular dynamics simulations, the compounds were observed in the formation of several chemical bonding of short bond distances. Additionally, the molecules remained in strong contact with the active pocket residues and experienced small conformation changes that seemed to be mediated by the CCR7 loops to properly engage the ligands. Two types of binding energy methods (MM/GBPBSA and WaterSwap) were additionally applied to further validate docking and simulation findings. Both analyses complement the good affinity of compounds for CCR7, the electrostatic and van der Waals energies being the most dominant in intermolecular interactions. The active pocket residue’s role in compounds binding was further evaluated via alanine scanning, which highlighted their importance in natural compounds binding. Additionally, the compounds fulfilled all drug-like rules: Lipinski, Ghose, Veber, Egan, and Muegge passed many safety parameters, making them excellent anti-cancer candidates for experimental testing.     

Phenolic Profile,EPR Determination,and Antiproliferative Activity against Human Cancer Cell Lines of Anthyllis vulneraria Extracts

In the current work, the leaf and flower extracts of Anthyllis vulneraria were evaluated for their chemical characterization using HPLC-MS and for their radical scavenging capacity toward methoxy radicals produced by a Fenton-type reaction using an electron paramagnetic resonance (EPR) spectroscopy assay. The in vitro antiproliferative activity of these extracts against several human-derived cancer cells (breast: MCF-7; cervical: HeLa; hepatocellular: HepG2) was also evaluated. The results showed that the Anthyllis vulneraria leaf extract was characterized by 17 different phenolic compounds, among which phenolic acids were the most abundant, while its flower extract exhibited higher contents of flavonoids. Furthermore, Anthyllis vulneraria extracts demonstrated a potent radical scavenging activity against methoxy radicals. Both extracts also significantly reduced the viability of the different cancer cell lines. The results of the current study suggested that Anthyllis vulneraria extracts are a promising source of antioxidant compounds with health benefits and pointed to their potential use for treating cancer and developing novel therapeutic agents.     

Effects of Regioisomerism on the Antiproliferative Activity of Hydroxystearic Acids on Human Cancer Cell Lines

A series of regioisomers of the hydroxystearic acid (HSA) was prepared, and the effect of the position of the hydroxyl group along the chain on a panel of human cancer cell lines was investigated. Among the various regioisomers, those carrying the hydroxyl at positions 5, 7, and 9 had growth inhibitor activity against various human tumor cell lines, including CaCo-2, HT29, HeLa, MCF7, PC3, and NLF cells. 10-HSA and 11-HSA showed a very weak effect. 8-HSA did not show inhibitory activity in all cell lines. The biological role of 7-HSA and 9-HSA is widely recognized, while little is known about the effects of 5-HSA. Therefore, the biological effects of 5-HSA in HeLa, HT29, MCF7, and NLF cell lines were investigated using the Livecyte’s ptychography technology, which allows correlating changes in proliferation, motility, and morphology as a function of treatment at the same time. 5-HSA not only reduces cell proliferation but also induces changes in cell displacement, directionality, and speed. It is important to characterize the biological effects of 5-HSA, this molecule being an important component of fatty acyl esters of hydroxy fatty acids (FAHFA), a class of endogenous mammalian lipids with noticeable anti-diabetic and anti-inflammatory effects.     

Phytochemistry and Biological Activity of Medicinal Plants in Wound Healing: An Overview of Current Research

Wound healing is a complicated process, and the effective management of wounds is a major challenge. Natural herbal remedies have now become fundamental for the management of skin disorders and the treatment of skin infections due to the side effects of modern medicine and lower price for herbal products. The aim of the present study is to summarize the most recent in vitro, in vivo, and clinical studies on major herbal preparations, their phytochemical constituents, and new formulations for wound management. Research reveals that several herbal medicaments have marked activity in the management of wounds and that this activity is ascribed to flavonoids, alkaloids, saponins, and phenolic compounds. These phytochemicals can act at different stages of the process by means of various mechanisms, including anti-inflammatory, antimicrobial, antioxidant, collagen synthesis stimulating, cell proliferation, and angiogenic effects. The application of natural compounds using nanotechnology systems may provide significant improvement in the efficacy of wound treatments. Increasing the clinical use of these therapies would require safety assessment in clinical trials.     

Ruthenium(II/III)‐Based Compounds with Encouraging Antiproliferative Activity against Non‐small‐Cell Lung Cancer

Hereby we present the synthesis of several ruthenium(II) and ruthenium(III) dithiocarbamato complexes. Proceeding from the Na[trans‐Ru^III(dmso)₂Cl₄] ( 2 ) and cis‐[Ru^II(dmso)₄Cl₂] ( 3 ) precursors, the diamagnetic, mixed‐ligand [Ru^IIL₂(dmso)₂] complexes 4 and 5 , the paramagnetic, neutral [Ru^IIIL₃] monomers 6 and 7 , the antiferromagnetically coupled ionic α‐[Ru^III₂L₅]Cl complexes 8 and 9 as well as the β‐[Ru^III₂L₅]Cl dinuclear species 10 and 11 (L=dimethyl‐ (DMDT) and pyrrolidinedithiocarbamate (PDT)) were obtained. All the compounds were fully characterised by elemental analysis as well as ¹H NMR and FTIR spectroscopy. Moreover, for the first time the crystal structures of the dinuclear β‐[Ru^III₂(dmdt)₅]BF₄ ? CHCl₃ ? CH₃CN and of the novel [Ru^IIL₂(dmso)₂] complexes were also determined and discussed. For both the mono‐ and dinuclear Ru^II and Ru^III complexes the central metal atoms assume a distorted octahedral geometry. Furthermore, in vitro cytotoxicity of the complexes has been evaluated on non‐small‐cell lung cancer (NSCLC) NCI‐H1975 cells. All the mono‐ and dinuclear Ru^III dithiocarbamato compounds (i.e., complexes 6 – 10 ) show interesting cytotoxic activity, up to one order of magnitude higher with respect to cisplatin. Otherwise, no significant antiproliferative effect for either the precursors 2 and 3 or the Ru^II complexes 4 and 5 has been observed.     

Cytotoxic Activity and Docking Studies of 2-arenoxybenzaldehyde N-acyl Hydrazone and 1,3,4-Oxadiazole Derivatives against Various Cancer Cell Lines

To understand whether previously synthesized novel hydrazone and oxadiazole derivatives have promising anticancer effects, docking studies and in vitro toxicity assays were performed on A-549, MDA-MB-231, and PC-3 cell lines. The antiproliferative properties of the compounds were investigated using molecular docking experiments. Each compound’s best-docked poses, binding affinity, and receptor-ligand interaction were evaluated. Compounds’ molecular weights, logPs, TPSAs, abilities to pass the blood-brain barrier, GI absorption qualities, and CYPP450 inhibition have been given. When the activities of these molecules were examined in vitro, for the A-549 cell line, hydrazone 1e had the minimum IC₅₀ value of 13.39 μM. For the MDA-MB-231 cell line, oxadiazole 2l demonstrated the lowest IC₅₀ value, with 22.73 μM. For PC-3, hydrazone 1d showed the lowest C50 value of 9.38 μM. The three most promising compounds were determined as compounds 1e, 1d, and 2a based on their minimum IC₅₀ values, and an additional scratch assay was performed for A-549 and MDA-MB-231 cells, which have high migration capacity, for the three most potent molecules; it was determined that these molecules did not show a significant antimetastatic effect.     

Serjanic Acid Glycosides from Chenopodium hybridum L. with Good Cytotoxicity and Selectivity Profile against Several Panels of Human Cancer Cell Lines

Two triterpene saponins, including a novel serjanic acid derivative, were isolated from Chenopodium hybridum L. (Amaranthaceae) aerial parts. Their structures were elucidated by a combination of spectroscopic methods (MS, 1D and 2D NMR). Both compounds were evaluated for cytotoxicity and selectivity on skin, prostate, gastrointestinal, thyroid and lung cancer cells. Their effect was dose and time-dependent with varied potency, the highest against prostate PC3 and melanoma WM793, where IC₅₀ was lower than the reference drug doxorubicin. Structure–activity relationship is briefly discussed.     

FerriIridium: A Lysosome‐Targeting Iron(III)‐Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells

Reported is the Fe^III‐activated lysosome‐targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta‐imino catechol group that can selectively bond to, and be oxidized by, free Fe^III inside the cell. Subsequent oxidative rearrangement releases Fe^II and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2‐hydroxybenzoquinone. Thus, Fe^II catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high Fe^III content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC₅₀=9.22 μm for AGS cells vs. >200 μm for LO2 cells). FerriIridium is the first metal‐based compound that has been developed for chemotherapy using Fe^III to enhance both selectivity and potency.     

Cytotoxic Properties of C17 Polyacetylenes from the Fresh Roots of Panax ginseng on Human Epithelial Ovarian Cancer Cells

Although C₁₇ polyacetylenes from Panax ginseng exhibit cytotoxic properties against various tumor cells, there have been few experiments on epithelial ovarian carcinoma cells. This study aimed to investigate the cytotoxic effects of C₁₇ polyacetylenes from P. ginseng against ovarian cancer cell lines. Four unreported (1–4) and fifteen known (5–19) C₁₇ polyacetylenes were obtained from the roots of P. ginseng using repeated chromatography (open column, MPLC, and preparative HPLC). The chemical structures of all the compounds were determined by analyzing their spectroscopic data (NMR, IR, and optical rotation) and HR-MS. The structures of new polyacetylenes were elucidated as (3S,8S,9R,10R)-(-)-heptadeca-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (1), (3S,8S,9R,10R)-(−)-heptadeca-1-en-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (2), (−)-haptadeca-9,10-epoxy-8-methoxy-4,6-diyne-3,11-diol (3), and (3R,9R,10R)-(+)-3-acetoxy-9,10-dihydroxyheptadeca-1-en-4,6-diyne (4), named ginsenoynes O, P, and Q, and 3-acetyl panaxytriol, respectively. Subsequently, in vitro experiments on A2780 and SKOV3 human epithelial ovarian carcinoma cells were performed to assess the cytotoxic properties of the isolates. Among the isolates, panaquinquecol 4 (15) exhibited the most remarkable cytotoxic effects on both human ovarian cancer cells A2780 (IC₅₀ value of 7.60 μM) and SKOV3 (IC₅₀ value of 27.53 μM). Therefore, C₁₇ polyacetylenes derived from P. ginseng may warrant further investigation for their therapeutic potential in epithelial ovarian cancer.     

LC-MS/MS-Based Metabolomic Profiling of Constituents from Glochidion velutinum and Its Activity against Cancer Cell Lines

This study aimed to establish the phytochemical profile of Glochidion velutinum and its cytotoxic activity against prostate cancer (PC-3) and breast cancer (MCF-7) cell lines. The phytochemical composition of G. velutinum leaf extract and its fractions was established with the help of total phenolic and flavonoid contents and LC-MS/MS-based metabolomics analysis. The crude methanolic extract and its fractions were studied for pharmacological activity against PC-3 and MCF-7 cell lines using the MTT assay. The total phenolic content of the crude extract and its fractions ranged from 44 to 859 µg GAE/mg of sample whereas total flavonoid contents ranged from 20 to 315 µg QE/mg of sample. A total of forty-eight compounds were tentatively dereplicated in the extract and its fractions. These phytochemicals included benzoic acid derivatives, flavans, flavones, O-methylated flavonoids, flavonoid O- and C-glycosides, pyranocoumarins, hydrolysable tannins, carbohydrate conjugates, fatty acids, coumarin glycosides, monoterpenoids, diterpenoids, and terpene glycosides. The crude extract (IC₅₀ = 89 µg/mL), the chloroform fraction (IC₅₀ = 27 µg/mL), and the water fraction (IC₅₀ = 36 µg/mL) were found to be active against the PC-3 cell line. However, the crude extract (IC₅₀ = 431 µg/mL), the chloroform fraction (IC₅₀ = 222 µg/mL), and the ethyl acetate fraction (IC₅₀ = 226 µg/mL) have shown prominent activity against breast cancer cells. Moreover, G. velutinum extract and its fractions presented negligible toxicity to normal macrophages at the maximum tested dose (600 µg/mL). Among the compounds identified through LC-MS/MS-based metabolomics analysis, epigallocatechin gallate, ellagic acid, isovitexin, and rutin were reported to have anticancer activity against both prostate and breast cancer cell lines and might be responsible for the cytotoxic activities of G. velutinum extract and its bioactive fractions.     

In Vitro Evaluation of Antiproliferative Properties of Novel Organotin(IV) Carboxylate Compounds with Propanoic Acid Derivatives on a Panel of Human Cancer Cell Lines

The synthesis of novel triphenyltin(IV) compounds, Ph₃SnLn (n = 1–3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), HL1, and the new propanoic acid derivatives 3-(4,5-bis(4-methoxylphenyl)oxazol-2-yl)propanoic acid, HL2, and 3-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)propanoic acid, HL3, has been performed. The ligands represent commercial drugs or their derivatives and the tin complexes have been characterized by standard analytical methods. The in vitro antiproliferative activity of both ligands and organotin(IV) compounds has been evaluated on the following tumour cell lines: human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29), breast cancer (MCF-7), and hepatocellular cancer (HepG2), as well as on normal mouse embryonic fibroblast cells (NIH3T3) with the aid of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. Contrary to the inactive ligand precursors, all organotin(IV) carboxylates showed very good activity with IC₅₀ values ranging from 0.100 to 0.758 µM. According to the CV assay (IC₅₀ = 0.218 ± 0.025 µM), complex Ph₃SnL1 demonstrated the highest cytotoxicity against the caspase 3 deficient MCF-7 cell line. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated a two-fold lower concentration of tin in MCF-7 cells in comparison to platinum. To investigate the mechanism of action of the compound Ph₃SnL1 on MCF-7 cells, morphological, autophagy and cell cycle analysis, as well as the activation of caspase and ROS/RNS and NO production, has been performed. Results suggest that Ph₃SnL1 induces caspase-independent apoptosis in MCF-7 cells.     

New Organometallic Ruthenium(II) Compounds Synergistically Show Cytotoxic,Antimetastatic and Antiangiogenic Activities for the Treatment of Metastatic Cancer

In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2′-bipyridine, 5,5′-dimethyl-2,2′-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC₅₀ values at the range of 3.3–15.0 μm . More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.