In-stent restenosis (ISR) is still a major concern in interventional cardiology. Drug coated balloon (DCB) angioplasty has been shown to be a promising option in treatment of ISR. However heterogeneity of different DCBs in suppression of neointimal growth has been described in a porcine model of coronary ISR. Therefore, in this registry analysis, we compared two frequently used paclitaxel eluting DCBs, the SeQuent Please and the Pantera Lux DCB.

Artemisinin is an anti-malarial drug with poor water solubility and oral absorption; so a variety of derivatives based on the parent nucleus have been developed. Compared with artemisinin, dihydroartemisinin (DHA) has a stronger anti-malaria activity, and has the advantages of high metabolic rate and better water solubility. Recent studies have discovered that DHA has a good inhibitory effect on tumor cells, which is closely related to the peroxide bridge in its molecular structure. Since tumor cells need more Fe3+ than normal cells, there are a large number of transferrin receptors on the tumor cell membrane. DHA can break the peroxide bridge in the presence of Fe2+, and the free radicals generated can play its lethal effect on tumor cells. In addition, DHA can promote endocytosis of transferrin receptor, and thus prevent cancer cells from taking Fe3+ from microenvironment. This article reviews the anti-tumor molecular mechanism of DHA, including accelerating oxidative damage, inducing apoptosis, inhibiting the growth, proliferation and invasion of tumor cells, reversing tumor multidrug resistance.

A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin. Active compounds of the series 8a-j were found to have sub-micromolar IC50 values selectively in Bcl-2 expressing human cancer cell lines; notably the 2-nitrophenyl analogue 8a was found to exhibit potent activity, and compounds 8a and 8e possessed comparable Bcl-2 binding affinity (ELISA assay) to the established natural product-based Bcl-2 inhibitor, gossypol. Molecular modeling studies helped to further rationalise anti-apoptotic Bcl-2 binding, and identified compounds 8a and 8e as candidates for further development as Bcl-2 inhibitory anticancer agents.

Four novel Pd2+ and Pt2+ mononuclear π-coordination compounds with general formula [M(HL)1,2Cl2], M=Pd2+, Pt2+ have been synthesized by reaction of [PdCl4]2-, [PtCl4]2- anions with N-allyl-4-morpholinethiocarboxamide (HL1) and N-Allyl-N'-tert-butylthiourea (HL2). All complexes have been characterized by single-crystal X-ray diffraction study and 1H, 13C NMR spectroscopy. Cytotoxic, cytostatic and proapoptotic activities of compounds have been determined in vitro on HeLa cell line and compared with cisplatin as etalon drug. All complex compounds possessed pronounced cytotoxic activity with IC50 indexes in range of 2·10-6-1.5·10-4М (IC50 of cisplatin is 5.7∙10-5М) and showed proapoptotic, cytostatic and antisyntetic influence higher or comparable with cisplatin. The comparative influence of cisplatin and synthesized metal complexes on pTZ19R* plasmid DNA was monitored by agarose gel electrophoresis. All compounds showed high affinity to DNA that correlates with observed cytostatic and proapoptotic levels. In general Pd(II) compounds showed higher activity than Pt(II) ones.

A technique using pulsed High Intensity Focused Ultrasound (HIFU) to destroy deep-seated solid tumors is a promising noninvasive therapeutic approach. A main purpose of this study was to design and test a HIFU transducer suitable for preclinical studies of efficacy of tested, anti-cancer drugs, activated by HIFU beams, in the treatment of a variety of solid tumors implanted to various organs of small animals at the depth of the order of 1-2cm under the skin. To allow focusing of the beam, generated by such transducer, within treated tissue at different depths, a spherical, 2-MHz, 29-mm diameter annular phased array transducer was designed and built. To prove its potential for preclinical studies on small animals, multiple thermal lesions were induced in a pork loin ex vivo by heating beams of the same: 6W, or 12W, or 18W acoustic power and 25mm, 30mm, and 35mm focal lengths. Time delay for each annulus was controlled electronically to provide beam focusing within tissue at the depths of 10mm, 15mm, and 20mm. The exposure time required to induce local necrosis was determined at different depths using thermocouples. Location and extent of thermal lesions determined from numerical simulations were compared with those measured using ultrasound and magnetic resonance imaging techniques and verified by a digital caliper after cutting the tested tissue samples. Quantitative analysis of the results showed that the location and extent of necrotic lesions on the magnetic resonance images are consistent with those predicted numerically and measured by caliper. The edges of lesions were clearly outlined although on ultrasound images they were fuzzy. This allows to conclude that the use of the transducer designed offers an effective noninvasive tool not only to induce local necrotic lesions within treated tissue without damaging the surrounding tissue structures but also to test various chemotherapeutics activated by the HIFU beams in preclinical studies on small animals.

Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.

Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.

Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in some patients, occurring any time during treatment and commonly characterized as mild to moderate in severity. Early identification of symptoms is essential in the proper management of pleural effusion. Prompt confirmation of diagnosis and management of pleural effusion can minimize morbidity and maximize the ability to preserve long-term clinical benefits with dasatinib. Here, we provide guidance on early identification and management of dasatinib-related pleural effusion.

Although chemoimmunotherapy prolongs survival and as such, is the standard of care for treatment-naïve patients, its effectiveness may be reduced by associated toxicity and dose reductions. In addition, it has been associated with the development of myelosuppression and secondary neoplasms; treatments are hence needed which offer greater survival and lowered toxicity. A range of new targeted agents, ibrutinib, idelalisib and venetoclax, have demonstrated such a balance in a second-line setting, offering CLL patients durable remissions and a modest toxicity profile. Ibrutinib has since been given first-line approval, and with news of second-generation targeted agents on the horizon, high-level discussions have taken place concerning their use in elderly or unfit patients; with potential use in younger patients in a first-line setting. This article reviews the potential first-line therapeutic options for treating CLL and their clinical potential and examines whether first-line chemotherapy has a place in the age of targeted agents.

Sensitizing the antitumor activity of monofunctional PtII complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional PtII complexes, in this study, the photosensitizing monofunctional PtII complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the PtII center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional PtII complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional PtII complex and renders the possibility of monofunctional PtII prodrugs for precise chemotherapy via only short time photoactivation.

Bioactive natural products play critical roles in modern drug development, especially anticancer agents. It has been widely reported that various pharmacological activities of such compounds are related to their antioxidant properties. Vanillin is a natural substance widely found in many plant species and often used in beverages, foods, cosmetics, and pharmaceutical products. Antioxidant and anticancer potential have been described for this compound. Considering the importance of vanillin in the area of human health and food and pharmaceuticals sectors, in this review, we discuss the role of vanillin on redox status and its potential contribution to the prevention and the treatment of cancer.

Rapamycin slows organismal aging and delays age-related diseases, extending lifespan in numerous species. In cells, rapamycin and other rapalogs such as everolimus suppress geroconversion from quiescence to senescence. Rapamycin inhibits some, but not all, activities of mTOR. Recently we and others demonstrated that pan-mTOR inhibitors, known also as dual mTORC1/C2 inhibitors, suppress senescent phenotype. As a continuation of these studies, here we investigated in detail a panel of pan-mTOR inhibitors, to determine their optimal gerosuppressive concentrations. During geroconversion, cells become hypertrophic and flat, accumulate lysosomes (SA-beta-Gal staining) and lipids (Oil Red staining) and lose their re-proliferative potential (RPP). We determined optimal gerosuppressive concentrations: Torin1 (30 nM), Torin 2 (30 nM), AZD8055 (100 nM), PP242 (300 nM), both KU-006379 and GSK1059615 (1000 nM). These agents decreased senescence-associated hypertrophy with IC50s: 20, 18, 15, 200 and 400 nM, respectively. Preservation of RPP by pan-mTOR inhibitors was associated with inhibition of the pS6K/pS6 axis. Inhibition of rapamycin-insensitive functions of mTOR further contributed to anti-hypertrophic and cytostatic effects. Torin 1 and PP242 were more "rapamycin-like" than Torin 2 and AZD8055. Pan-mTOR inhibitors were superior to rapamycin in suppressing hypertrophy, senescent morphology, Oil Red O staining and in increasing so-called "chronological life span (CLS)". We suggest that, at doses lower than anti-cancer concentrations, pan-mTOR inhibitors can be developed as anti-aging drugs.

We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARα target genes, we tested and found that PPARα itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARα/γ agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance.

In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50 value of 7.1 μM.

This narrative review focuses on the role of sarcopenia and chemotherapy-induced toxicity in cancer patients. Consistent evidence shows that sarcopenia in cancer patients leads to decreased overall survival by influencing treatment discontinuation and dose reduction. Therefore, sarcopenia should be considered a robust prognostic factor of negative outcome as well as a determinant of increased healthcare costs. RESUMO Esta revisão narrativa descreve o papel da sarcopenia e a toxicidade mediada pela quimioterapia em pacientes com câncer. Diversas evidências consistentes mostram que a sarcopenia em pacientes com câncer induz à menor sobrevida global, por influenciar na interrupção do tratamento e na redução da dose. Portanto, a sarcopenia pode ser considerada um importante fator de prognóstico de desfecho negativo, além de um determinante de maiores custos em saúde.

Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients. We performed an update of the literature about the criteria for choosing AD in women receiving Tmf. Tricyclic AD, paroxetine and fluoxetine should be avoided in patients receiving Tmf, because they are strong inhibitors of CYP2D6. Bupropion, duloxetine and sertraline are only moderate inhibitors of the cytochrome and are not contraindicated. Citalopram, desvenlafaxine, escitalopram, milnacipran and venlafaxine are recommended, because they do not influence the metabolism and clinical efficacy of Tmf and have fewer drug interactions. However, other additional pharmacological and clinical issues should be considered when choosing an antidepressant in women with breast cancer.

Recently various drug candidates with excellent anticancer potency have been demonstrated, whereas their clinical application largely suffers from several limitations especially poor solubility. Ursolic acid (UA) as one of ubiquitous pentacyclic triterpenes in plantkingdom exhibited versatile antiproliferative effects in various cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for its clinical development. With the aim of development of novel derivatives with enhanced potency, a series of diversified UA amphiphiles have been designed, synthesized, and pharmacologically evaluated. Amphiphile 10 (FZU-03,010) with significant improved antiproliferative effect can self-assemble into stable nanoparticles in water, which may serve as a promising candidate for further development.

20-(S)-Camptothecin (CPT) is a natural alkaloid extracted from the bark of Camptotheca acuminata (Chinese happy tree). It acts as a DNA topoisomerase 1 poison with an interesting antitumor activity and its use is limited by low stability and solubility and unpredictable drug-drug interactions. Since the late 20th century, it has been widely used in cancer therapy and, since extraction yields from plant tissues are very low, various synthetic routes have been developed to satisfy the increase in demand for CPT. Moreover, SAR studies have allowed for the development of more potent CPT analogues topotecan and irinotecan. Unfortunately, resistance has already occurred in several tumour lines. Additional studies are needed to better understand the relationship between substituents and resistance, its clinical relevance and the impact of related gene polymorphism. One of the latest research approaches focuses on modifying the delivery mode to improve tumour cell uptake and reduce toxicity.

The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling.