Potent Antiproliferative Drugs Research Articles

A novel, glutathione-activated prodrug of pimasertib loaded in liposomes for targeted cancer therapy.

Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its in vitro biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug.

Potent and Selective Benzothiazole-Based Antimitotics with Improved Water Solubility: Design, Synthesis, and Evaluation as Novel Anticancer Agents.

The design of colchicine site ligands on tubulin has proven to be a successful strategy to develop potent antiproliferative drugs against cancer cells. However, the structural requirements of the binding site endow the ligands with low aqueous solubility. In this work, the benzothiazole scaffold is used to design, synthesize, and evaluate a new family of colchicine site ligands exhibiting high water solubility. The compounds exerted antiproliferative activity against several human cancer cell lines, due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HEK-293 cells, as evidenced by MTT and LDH assays. The most potent derivatives, containing a pyridine moiety and ethylurea or formamide functionalities, displayed IC50 values in the nanomolar range even in the difficult-to-treat glioblastoma cells. Flow cytometry experiments on HeLa, MCF7, and U87MG cells showed that they arrest the cell cycle at the G2/M phases at an early time point (24 h), followed by apoptotic cell death 72 h after the treatment. Tubulin binding was confirmed by microtubule network disruption observed via confocal microscopy. Docking studies support favorable interaction of the synthesized ligands at the colchicine binding site. These results validate the proposed strategy to develop potent anticancer colchicine ligands with improved water solubility.

Mycophenolic acid pharmacogenomics in kidney transplantation

Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed to prevent acute rejection in kidney transplantation. MPA reversibly inhibits the enzymes involved in the synthesis of guanosine nucleotides, thus preventing DNA replication of immune cells. Consequently, the repression of both cell and humoral immunity induces renal allograft tolerance. MPA is an effective and safe immunosuppressive drug, but some patients show variability in drug concentration, acute rejection, graft dysfunction, or MPA-related adverse events. Although the pharmacogenomics of immunosuppressive drugs has been widely investigated, MPA has been explored to a lesser extent. This review of MPA pharmacogenomic studies, included pharmacokinetics, adverse events, and main clinical outcomes of MPA treatment in kidney transplantation. Associations of variants in genes encoding MPA metabolizing enzymes, transporters, and targets with drug efficacy and safety are described. Most pharmacogenetic studies have focused on small sample sizes and few simultaneously analyzed genetic variants. Some studies reported significant associations of pharmacokinetics- and pharmacodynamics-related genes with MPA exposure, acute rejection, graft dysfunction, hematological events, and gastrointestinal complications. However, even large cohorts did not replicate the findings, possibly due to divergent study design, immunosuppressive scheme, follow-up time, and other factors. Finally, the heterogeneity of aspects between studies limit conclusions on pharmacogenetic biomarkers of MPA in kidney transplantation.

In vitro biological properties and predicted DNA–BSA interaction of three new dicyanidoargentate(i)-based complexes: synthesis and characterization

The synthesis, characterization and biological activity of three novel dicyanidoargentate(i)-based complexes are reported. The in vitro results show that these complexes may be potent antiproliferative drug candidates.

Performance of the XLIMUS Sirolimus‐Eluting Coronary Stent in Very Complex Lesions

Stent delivery failure may occur especially when treating complex coronary artery stenosis. XLIMUS (CARDIONOVUM GmbH, Bonn, Germany) is a new sirolimus-eluting stent (SES) with the following features: 1) cobalt chromium stent platform, with low (73 μm) strut thickness, (2) biodegradable polymer, and 3) potent antiproliferative drug (Sirolimus). Preliminary data suggest that XLIMUS SES may be ideal for the treatment of complex lesions. In this registry, we assessed the deliverability, safety, and efficacy of percutaneous coronary interventions (PCI) using the XLIMUS SES in patients undergoing elective PCI in native coronary vessels for complex de novo lesions, including severe calcification, severe tortuosity, and chronic total occlusion. The primary objective of the study is the delivery success of the XLIMUS SES. The secondary objective is the 1-year rate of major adverse cardiac events (MACE; including all-cause death, nonfatal myocardial infarction, and repeat revascularization). A total of 200 consecutive patients with 255 lesions were included. Delivery success was obtained in 196 (98%) patients and in 251 (98.4%) lesions. The XLIMUS SES was successfully implanted on the first attempt with a single guidewire in 176 (88%) patients and in 208 (81.6%) lesions. Additional techniques to facilitate stent delivery (i.e., buddy wire, anchoring-balloon, or GuideLiner catheter) were necessary in 47 (18.4%) lesions. Failure in XLIMUS SES implantation occurred in 4 (1.6%) lesions. MACE rate at 1 year was 9%. This registry supports the positive performance of the XLIMUS SES in the treatment of complex coronary artery lesions.

Abstract 5294: Inhibition of mitochondrial transport in neuronal cells by microtubule-targeting drugs eribulin, ixabepilone, paclitaxel, and vincristine

Abstract Peripheral neuropathy can be a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. We hypothesize that inhibition of mitochondrial transport contributes to the neuropathic “dying back” of peripheral neurons often seen with chemotherapy-induced peripheral neuropathy. We examined the effects of eribulin (ERB), vincristine (VCR), paclitaxel (PAC), and ixabepilone (IXA) on mitochondrial trafficking in neurites of SK-N-SH human neuroblastoma cells. The concentration range used was chosen to reflect their relative potencies for inhibition of cancer cell proliferation (3× IC50: ERB, 2.4 nM, VCR, 8.4 nm, IXA, 23 nM, PAC, 33nM). In control cells, mitochondria moved anterogradely at a velocity of 14 µm/min, and retrogradely at 16 µm/min. At ∼ 3× IC50 antiproliferative values, ERB and VCR did not significantly inhibit anterograde trafficking velocity, whereas IXA and PAC reduced it by 30%. At sufficiently high concentrations, ERB (10 nM, 10× IC50) and VCR (10 nM, 4× IC50) reduced anterograde velocity to the same extent as PAC and IXA, by ∼30%. Retrograde trafficking was not significantly inhibited by any of the drugs. The drugs also reduced the number of moving mitochondria. In control cells, an average of 4.3 mitochondria moved per visualized cell area. The four drugs, over a range of the concentrations, reduced the number of moving mitochondria by 19-47%, with no apparent differences between drugs. FCCP (10 µM), a mitochondrial membrane depolarizing compound, also reduced the number of moving mitochondria by 39%, but, interestingly, did not inhibit the mitochondrial trafficking velocity. The more potent antiproliferative drugs ERB and VCR did not inhibit mitochondrial trafficking velocity at 3× IC50 concentrations, while the less potent antiproliferative drugs PAC and IXA inhibited anterograde trafficking velocity. This may be due in part to differences in drug-microtubule binding; ERB and VCR bind primarily to microtubule ends, while TAX and IXA bind along the lengths of the microtubules. Additionally, structural effects on microtubules, such as bundling, curved microtubules, and shortened microtubules, may influence the ability of kinesin to “walk” along the microtubule surface. All four drugs reduced the number of moving mitochondria, possibly as a result of mitochondrial depolarization, suggested by the effects of the mitochondrial depolarizing compound, FCCP. These results suggest that the antiproliferative potency of the drugs, as well as the binding location on microtubules and/or drug-induced changes in microtubule structure, contribute to the drugs' neurotoxic effects on mitochondrial trafficking velocity in the axons of peripheral neurons, while the increase in stalled mitochondria may be due to a mitochondrial depolarization effect of the drugs. This work was funded by Eisai Inc. Note: This abstract was not presented at the meeting. Citation Format: Jennifer A. Smith, Gregoriy Smiyun, Leslie Wilson, Stuart Feinstein, Mary Ann Jordan. Inhibition of mitochondrial transport in neuronal cells by microtubule-targeting drugs eribulin, ixabepilone, paclitaxel, and vincristine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5294. doi:10.1158/1538-7445.AM2014-5294

In vitro study of dual drug-eluting stents with locally focused sirolimus and atorvastatin release

Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70% respectively 90% of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.

Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents

As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED50 values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC50 values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED50 values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC50 values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43−45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents.

Antiproliferative Activity of Violaxanthin Isolated from Bioguided Fractionation of Dunaliella tertiolecta Extracts

Dunaliella tertiolecta (DT) was chemically investigated to isolate molecules inhibiting cancer cell proliferation and inducing apoptosis in vitro. The potency to inhibit cell growth was used for the bio-guided fractionation and isolation of active compounds using chromatographic techniques. The DT dichloromethane extract exhibited a strong anti-proliferative activity on MCF-7 and LNCaP cells, and was further fractionated and sub-fractionated by RP-HPLC. High resolution mass spectrometry and spectrophotometric analysis unequivocally identified violaxanthin as the most antiproliferative molecule present in DT DCM extract. Violaxanthin purified from DT induced MCF-7 dose-dependent growth inhibition in continuous and discontinuous treatments, at concentrations as low as 0.1 μg·mL−1 (0.17 μM). Phosphatidylserine exposure, typical of early apoptosis, was observed after 48 h treatment at 8 μg·mL−1 (13.3 μM) but no DNA fragmentation, characteristic of late apoptosis steps, could be detected even after 72 h treatment at 40 μg·mL−1 (66.7 μM). Taken together, our results demonstrate the strong antiproliferative activity of violaxanthin on one human mammary cancer cell line, and suggest that studying the pharmacology of violaxanthin and pharmacomodulated derivatives on cancer cells may allow potent antiproliferative drugs to be obtained.

Minimally Invasive Kidney Transplantation: The First Experience

Minimally invasive procedures in recent years have gained widespread acceptance. Within the field of transplantation, laparoscopic living donor nephrectomy (LLDN), requiring a 6- to 10-cm incision, is now considered the optimal procedure. According to recent MEDLINE searches, no minimally invasive technique has been reported for kidney transplantation. Considering the rapid evolution of minimally invasive surgery during the last decade, there is little reason to believe that kidney transplantation in future will be excluded from this development. A novel minimally invasive technique for kidney transplantation (MIKT) is presented, restricted to a 7- to 9-cm incision and minimal dissection/tissue trauma. The kidney is meticulously prepared on the back table and placed in a fitted lateral, retroperitoneal pouch. All three anastomoses are performed with the kidney in its final “in situ” position, and ureter reimplantation is done by extravesical technique. Twenty-one patients have been transplanted by MIKT and followed in a prospective manner, along with a matched control group subjected to conventional kidney transplantation. Our results indicate that MIKT may be executed safely and quickly. Beneficial effects on postoperative pain/analgesia, recovery, and complications are suggested by this first MIKT experience. The technical solutions of MIKT are per se not unique. However, the incision is minimal and not larger than the one required for LLDN. Minimally invasive surgery seems particularly attractive in the immunosuppressed population, and even more so with the recent introduction of potent antiproliferative drugs.