L1210 Cells Research Articles

Cell Death Effects Induced by Sulforaphane and Allyl Isothiocyanate on P-Glycoprotein Positive and Negative Variants in L1210 Cells.

Variants of L1210 leukemia cells-namely, parental P-glycoprotein-negative S cells and R and T cells expressing P-glycoprotein, due to selection with vincristine and transfection with the human p-glycoprotein gene, respectively-were used. The responses of these cell variants to two naturally occurring isothiocyanates-sulforaphane (SFN, from cruciferous vegetables) and allyl isothiocyanate (AITC, from mustard, radish, horseradish and wasabi)-were studied. We obtained conflicting results for the cell death effects induced by isothiocyanates, as measured by i. cell counting, which showed inhibited proliferation, and ii. cell metabolic activity via an MTS assay, which showed an increased MTS signal. These results indicated the hyperactivation of cell metabolism induced by treatment with isothiocyanates. In more detailed study, we found that, depending on the cell variants and the isothiocyanate used in treatment, apoptosis and necrosis (detected by annexin-V cells and propidium iodide staining), as well as autophagy (detected with monodansylcadaverine), were involved in cell death. We also determined the cell levels/expression of Bcl-2 and Bax as representative anti- and pro-apoptotic proteins of the Bcl-2 family, the cell levels/expression of members of the canonical and noncanonical NF-κB pathways, and the cell levels of 16 and 18 kDa fragments of LC3B protein as markers of autophagy.

Overexpression of GRP78/BiP in P-Glycoprotein-Positive L1210 Cells is Responsible for Altered Response of Cells to Tunicamycin as a Stressor of the Endoplasmic Reticulum.

P-glycoprotein (P-gp, ABCB1 member of the ABC (ATP-binding cassette) transporter family) localized in leukemia cell plasma membranes is known to reduce cell sensitivity to a large but well-defined group of chemicals known as P-gp substrates. However, we found previously that P-gp-positive sublines of L1210 murine leukemia cells (R and T) but not parental P-gp-negative parental cells (S) are resistant to the endoplasmic reticulum (ER) stressor tunicamycin (an N-glycosylation inhibitor). Here, we elucidated the mechanism of tunicamycin resistance in P-gp-positive cells. We found that tunicamycin at a sublethal concentration of 0.1 µM induced retention of the cells in the G1 phase of the cell cycle only in the P-gp negative variant of L1210 cells. P-gp-positive L1210 cell variants had higher expression of the ER stress chaperone GRP78/BiP compared to that of P-gp-negative cells, in which tunicamycin induced larger upregulation of CHOP (C/EBP homologous protein). Transfection of the sensitive P-gp-negative cells with plasmids containing GRP78/BiP antagonized tunicamycin-induced CHOP expression and reduced tunicamycin-induced arrest of cells in the G1 phase of the cell cycle. Taken together, these data suggest that the resistance of P-gp-positive cells to tunicamycin is due to increased levels of GRP78/BiP, which is overexpressed in both resistant variants of L1210 cells.

Antiproliferative Activity of Extracts and Fractions from Irradiated Curcuma zanthorrhiza Rhizomes Against Mouse Leukemia and Human Cancer Cell Lines

Curcuma zanthorrhiza Roxb. is a medicinal plant that is used as a raw material in the herbal medicine and pharmaceutical industries. The main content of C. zanthorrhiza is curcuminoid, which is used as an antioxidant and an anticancer agent. The aim of this research was to study the effect of gamma radiation used for preserving simplicia or herbal drugs through the examination of their cytotoxicity against mouse leukemia L1210 cells and antiproliferative activity against human cancer cell lines HUT78, A549, HeLa, and THP1. The samples of curcuma rhizome were irradiated by gamma ray emitted by Cobalt-60 as a source at doses of 0 (control), 5, 7.5, 10, and 15 kGy. After irradiation, the samples were macerated using n -hexane, ethyl acetate, and ethanol, respectively. Preliminary cytotoxicity test toward extract from control sample against mouse leukemia L1210 cells revealed that the ethyl acetate extract was the most active extract inhibiting the growth of cells with an IC 50 value of 16.6 µg/mL, followed by ethanol extract (18.8 µg/mL) and n -hexane extract (42.7 μg/mL). Fractionation using a chromatography column of the ethyl acetate extract resulted in seven fractions denoted as F1-F7. The cytotoxicity test of the seven fractions against mouse leukemia L1210 cells showed that fraction 3 (F3) was the most active fraction with an IC 50 value of 10.0 μg/mL, followed by F7 (11.2 μg/mL), F6 (11.8 μg/mL), F5 (12.0 μg/mL), F1 (13.2 μg/mL), F4 (14.5 μg/mL), and F2 (27.8 μg/mL), respectively. Based on these results, all irradiated samples were then extracted, fractionated, and tested for cytotoxicity in a similar manner. The result showed that irradiation of samples under doses up to 10 kGy can be used to preserve Curcuma zanthorrhiza simplicia without damaging its efficacy. To ensure that the irradiation dose of 10 kGy did not reduce anticancer activity, the F3 from the irradiated sample at a dose of 10 kGy was also examined of its in-vitro antiproliferative activity using HUT78, A549, HeLa, and THP1 human cancer cell lines. The results showed that irradiation of the sample at a dose of 10 kGy reduced the antiproliferative activity of F3 against HUT78 (32 %), A549 (48 %), HeLa (42 %), and THP1 (31 %). However, its reduction did not eliminate its antiproliferative activities. These results indicated that the preservation of simplicia using radiation can be done at a maximum radiation dose of 10 kGy by modifying the concentration of simplicia in the fabrication process of herbal medicine formulation.

Mast Cells May Differentially Regulate Growth of Lymphoid Neoplasms by Opposite Modulation of Histamine Receptors.

Cancer microenvironment is complex and consists of various immune cells. There is evidence for mast cell (MC) infiltration of tumors, but their role thereof is poorly understood. In this study, we explored the effects of mast cell and their mediators on the growth of hematological cancer cells. The affect is demonstrated using RBL-2H3 MCs, and YAC-1, EL4 and L1210 as hematological cancer cell lines. Direct contact with MCs or stimulation by their mediators caused growth inhibition of YAC-1 cells, growth enhancement of EL4 cells and no change in growth of L1210 cells. This effect was confirmed by cancer cell recovery, cell viability, mitochondrial health, and cell cycle analysis. MCs showed mediator release in direct contact with tumor cells. MC mediators' treatment to YAC-1 and EL4 yielded exactly opposite modulations of survival markers, Survivin and COX-2 and apoptosis markers, Caspase-3, Bcl-2, in the two cell lines. Histamine being an important MC mediator, effect of histamine on cell recovery, survival markers and expression of various histamine receptors and their modulation in cancer cells was studied. Again, YAC-1 and EL4 cells showed contrary histamine receptor expression modulation in response to MC mediators. Histamine receptor antagonist co-treatment with MC mediators to the cancer cells suggested a major involvement of H2 and H4 receptor in growth inhibition in YAC-1 cells, and contribution of H1, H2, and H4 receptors in cell growth enhancement in EL4 cells. L1210 showed changes in the histamine receptors' expression but no effect on treatment with receptor antagonists. It can be concluded that anti-cancerous action of MCs or their mediators may include direct growth inhibition, but their role may differ depending on the tumor.

Total Synthesis of (-)-Himeradine A.

(-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.

Total Synthesis of (−)‐Himeradine A

Abstract(−)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2,4,6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (−)‐Himeradine A was prepared in 17 steps in the longest linear sequence.

Core‐Shell Functionalized Zirconium‐Pemetrexed Coordination Nanoparticles as Carriers with a High Drug Content

AbstractSelected drug molecules with Lewis base functions can be assembled into coordinative nanoparticles (NPs) by linking them with suitable metal ions. Such nanomaterials exhibit a high material economy due to high drug contents and minor amounts of inactive additives. The antifolate pemetrexed (PMX) which is used for the treatment of lung cancers contains two carboxy functions that are able to undergo coordinative binding of metal ions. This study presents the development of a multilayer PMX NP system where each layer serves a distinct purpose. The metal‐drug NP core is assembled in a bottom‐up approach by coordinative interactions between zirconium (IV) ions and PMX molecules. Since the NP core is generated from drug molecules as essential units, it features a very high drug content of almost 80%. The NP core is stabilized against serum with a shell of a polymerized oligoamine‐modified trimethoxysilane derivative (TMSP). As external layer, a polyglutamate‐block‐polysarcosine‐N3 (pGlu‐b‐pSar) coating mediates efficient colloidal stabilization and enables introduction of targeting functionalities by click chemistry. Attaching folate or transferrin ligands to the polymer layer enhances NP uptake into target receptor positive KB and L1210 cells. This study illustrates the development and characterization of metal‐drug coordination NPs with high drug content and variable external functionalizations.

MTORC1/2 Inhibitor Served as a More Ideal Agent Against the Growth of Mouse Lymphocytic Leukemia Both In Vitro and In Vivo.

Chronic lymphocytic leukemia (CLL) still remains an incurable disease as the cells evade apoptosis, which is an obstacle for current therapeutic approaches. Therefore, our aim was to identify an ideal target of leukemic cell growth for developing inhibitors. Mouse lymphocytic leukemia cell line L1210, human Toledo cells and a DBA/2 mouse graft model were used to analyze the activity of dual mTORC1/2 inhibitor AZD2014s. Western blotting and flow cytometry were performed to determine the mechanism. AZD2014 inhibited L1210 and human Toledo cell proliferation. Treatment with AZD2014 reduced the phosphorylation levels of S6K1 and 4EBP1 and the protein levels of Rictor, a component of the mTORC2 pathway. AZD2014 induced cell cycle arrest at the G0-G1 phase by reducing the expression of cyclin D1 and CDK4. Oral administration of AZD2014 significantly inhibited the growth of L1210 cell grafts in DBA/2 mice. The mTORC1/2 inhibitor may be a better therapeutic agent compared to PI3K/mTORC1 inhibitors for treating patients with CLL.

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

Progress towards the Total Syntheses of Lycopodium Alkaloid, Lycopladine A

AbstractSeveral alkaloids derived from discrete Lycopodium species can treat Alzheimer's disease and increase the efficiency of learning and memory in animals. Thus, Lycopodium alkaloids bearing amazingly unique hetero‐polycyclic ring scaffolds persuaded scientists to look upon its biogenetic and biosynthetic pathways and to design its ambitious total syntheses. Recently, a C16N type Lycopodium alkaloid, (+)‐lycopladine A; isolated from the club moss Lycopodium complanatum, showed selective but modest cytotoxicity towards murine lymphoma L1210 cells (IC50 7 μg/mL). Owing to its dense array of stereochemical features, as well as intriguing biological activity, lycopladine A has been an important synthetic target for last 12 years. An overview of the synthetic studies of lycopladine A is presented, covering literature from 2006 until March 2019.

Antioxidant and anticancer activity of Eleutherine bulbosa (Mill.) Urb on leukemia cells L1210

Antioxidant and anticancer activity test on Leukemia cells L1210 were carried out on four fractions (ethanol extract, n-hexane, chloroform, and water fraction) of Eleutherine bulbosa [Mill.] Urb. The purpose of this research is to obtain IC50 antioxidant and anticancer activity of the active fraction of Eleutherine. bulbosa [Mill.] Urb on Leukemia cells L1210. The research method includes antioxidant activity test with DPPH (2,2-diphenyl-1-picrylhydrazyl) method, anticancer activity test of active fraction on Leukemia cell L1210, and GC-MS analysis to determine the active compound. Chloroform fraction has the best antioxidant activity with IC50 value 19.694 ppm (very strong category). The IC50 value of the chloroform fraction on L1210 Leukemia cells was 9.56 ppm (very strong category). Based on GC-MS analysis of the chloroform fraction, some compounds such as hexadecanoic acid, 9,12-octadecadienoic acid, linolenic acid, octadecanoic acid, androstan-17-one, and 1-(2,3,5,6-tetramethylphenyl)- ethanone were detected.

Screening of Phenanthroquinolizidine Alkaloid Derivatives for Inducing Cell Death of L1210 Leukemia Cells with Negative and Positive P-glycoprotein Expression.

We describe the screening of a set of cryptopleurine derivatives, namely thienoquinolizidine derivatives and (epi-)benzo analogs with bioactive phenanthroquinolizidine alkaloids that induce cytotoxic effects in the mouse lymphocytic leukemia cell line L1210. We used three variants of L1210 cells: i) parental cells (S) negative for P-glycoprotein (P-gp) expression; ii) P-glycoprotein positive cells (R), obtained by selection with vincristine; iii) P-glycoprotein positive cells (T), obtained by stable transfection with a human gene encoding P-glycoprotein. We identified the most effective derivative 11 with a median lethal concentration of ≈13 μM in all three L1210 cell variants. The analysis of the apoptosis/necrosis induced by derivative 11 revealed that cell death was the result of apoptosis with late apoptosis characteristics. Derivative 11 did not induce a strong alteration in the proportion of cells in the G1, S or G2/M phase of the cell cycle, but a strong increase in the number of S, R and T cells in the subG1 phase was detected. These findings indicated that we identified the most effective inducer of cell death, derivative 11, and this derivative effectively induced cell death in S, R and T cells at similar inhibitory concentrations independent of P-gp expression.

Synthesis, Biological Evaluation and Ligand Based Pharmacophore Modeling of New Aromatic Thiosemicarbazones as Potential Anticancer Agents.

Two series of new aromatic thiosemicarbazone derivatives were synthesized by condensation of N-(4-cyanophenyl)hydrazine carbothioamide (I) and N-(4-methylsulfanylphenyl)hydrazine carbothioamide (II) with appropriate aromatic aldehydes in order to investigate their antiviral and cytostatic potency. The chemical structures of all compounds were fully characterized by elemental analysis and spectroscopic techniques. The results of the bioassays indicated that compounds Id, Ie, If and IIf proved inhibitory against influenza virus A (EC50 = 13 – 27 μg/mL for strain H1N1 and 9.3 – 18 μg/mL for strain H3N2). Compounds Ig and IIg were the most cytostatic compounds with inhibition of HeLa cell proliferation at an IC50 = 0.3 μg/mL for Ig and 1.9 μg/mL for IIg. Especially, compound Ig showed the highest cytostatic activity with IC50 of 0.30, 0.70 and 2.50 μg/mL against HeLa, CEM and L1210 cell lines, respectively. This inhibition range was within the same order of magnitude as that for cisplatin. Furthermore, molecular modeling was carried out to examine the cytostatic activity and determine the best pharmacophore model as a guide for the design and development of potential prodrugs in future studies.

Combination Chemotherapy of L1210 Tumors in Mice with Pretubulysin and Methotrexate Lipo-Oligomer Nanoparticles.

In the current study, nanoparticles containing the antimetabolite drug methotrexate (MTX) and the novel tubulin-binding drug pretubulysin (PT) were developed for combination chemotherapy. Polyelectrolyte complexes were formed based on ∼20 nm cationic nanomicelles of lipo-oligomer 454 with the anionic MTX at the molar ratio of 3:1, resulting in spherical nanoparticles with sizes of 150 nm (454 MTX). Particle formation in the presence of PT, which also interacts with 454, resulted in coloaded micelle complexes (454 PT+MTX) of 170 nm as demonstrated by transmission electron microscopy and dynamic light scattering measurements. Both drugs were incorporated to a high extent (∼85% for MTX, ∼70% for PT). Nanoparticles were stable in up to 20% serum and physiological NaCl solution. Cellular internalization of 454 PT+MTX into L1210 leukemia and KB cervix carcinoma cells was determined by confocal light scattering microscopy. The antitumor activity of the drug combination PT+MTX in both cell lines was strongly increased by drug formulation with 454 with IC50 values of PT+MTX decreasing 11-fold from 0.22 nM to 19 pM on L1210 cells and 6-fold from 2.8 to 0.48 nM on KB cervix carcinoma cells. Systemic treatment of NMRI nu/nu mice bearing subcutaneous L1210 tumors with 454 PT+MTX nanoparticles resulted in a more effective delay of tumor growth in comparison to the free drug combination of PT+MTX without 454. Importantly, nanoparticle formulation of PT+MTX with 454 increased the survival of mice by more than 100% compared to that of the buffer treated group and more than 40% compared to that of the free drug group.

Soritesidine, a Novel Proteinous Toxin from the Okinawan Marine Sponge Spongosorites sp.

A novel protein, soritesidine (SOR) with potent toxicity was isolated from the marine sponge Spongosorites sp. SOR exhibited wide range of toxicities over various organisms and cells including brine shrimp (Artemia salina) larvae, sea hare (Aplysia kurodai) eggs, mice, and cultured mammalian cells. Toxicities of SOR were extraordinary potent. It killed mice at 5 ng/mouse after intracerebroventricular (i.c.v.) injection, and brine shrimp and at 0.34 µg/mL. Cytotoxicity for cultured mammalian cancer cell lines against HeLa and L1210 cells were determined to be 0.062 and 12.11 ng/mL, respectively. The SOR-containing fraction cleaved plasmid DNA in a metal ion dependent manner showing genotoxicity of SOR. Purified SOR exhibited molecular weight of 108.7 kDa in MALDI-TOF MS data and isoelectric point of approximately 4.5. N-terminal amino acid sequence up to the 25th residue was determined by Edman degradation. Internal amino acid sequences for fifteen peptides isolated from the enzyme digest of SOR were also determined. None of those amino acid sequences showed similarity to existing proteins, suggesting that SOR is a new proteinous toxin.

Combined antitumoral effects of pretubulysin and methotrexate.

Pretubulysin (PT), a potent tubulin‐binding antitumoral drug, and the well‐established antimetabolite methotrexate (MTX) were tested separately or in combination (PT+MTX) for antitumoral activity in L1210 leukemia cells or KB cervix carcinoma cells in vitro and in vivo in NMRI‐nu/nu tumor mouse models. In cultured L1210 cells, treatment with PT or MTX displays strong antitumoral effects in vitro, and the combination PT+MTX exceeds the effect of single drugs. PT also potently kills the MTX resistant KB cell line, without significant MTX combination effect. Cell cycle analysis reveals the expected arrest in G1/S by MTX and in G2/M by PT. In both cell lines, the PT+MTX combination induces a G2/M arrest which is stronger than the PT‐triggered G2/M arrest. PT+MTX does not change rates of apoptotic L1210 or KB cells as compared to single drug applications. Confocal laser scanning microscopy images show the microtubule disruption and nuclear fragmentation induced by PT treatment of L1210 and KB cells. MTX changes the architecture of the F‐actin skeleton. PT+MTX combines the toxic effects of both drugs. In the in vivo setting, the antitumoral activity of drugs differs from their in vitro cytotoxicity, but their combination effects are more pronounced. MTX on its own does not display significant antitumoral activity, whereas PT reduces tumor growth in both L1210 and KB in vivo models. Consistent with the cell cycle effects, MTX combined at moderate dose boosts the antitumoral effect of PT in both in vivo tumor models. Therefore, the PT+MTX combination may present a promising therapeutic approach for different types of cancer.

Mode of photoexcited C60 fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells.

Introduction: C60 fullerene has received great attention as a candidate for biomedical applications. Due to unique structure and properties, C60 fullerene nanoparticles are supposed to be useful in drug delivery, photodynamic therapy (PDT) of cancer, and reversion of tumor cells’ multidrug resistance. The aim of this study was to elucidate the possible molecular mechanisms involved in photoexcited C60 fullerene-dependent enhancement of cisplatin toxicity against leukemic cells resistant to cisplatin. Methods: Stable homogeneous pristine C60 fullerene aqueous colloid solution (10-4 М, purity 99.5%) was used in the study. The photoactivation of C60 fullerene accumulated by L1210R cells was done by irradiation in microplates with light-emitting diode lamp (420-700 nm light, 100 mW·cm-2). Cells were further incubated with the addition of Cis-Pt to a final concentration of 1 μg/mL. Activation of p38 MAPK was visualized by Western blot analysis. Flow cytometry was used for the estimation of cells distribution on cell cycle. Mitochondrial membrane potential (Δψm) was estimated with the use of fluorescent potential-sensitive probe TMRE (Tetramethylrhodamine Ethyl Ester). Results: Cis-Pt applied alone at 1 μg/mL concentration failed to affect mitochondrial membrane potential in L1210R cells or cell cycle distribution as compared with untreated cells. Activation of ROS-sensitive proapoptotic p38 kinase and enhanced content of cells in subG1 phase were detected after irradiation of L1210R cells treated with 10-5M C60 fullerene. Combined treatment with photoexcited C60 fullerene and Cis-Pt was followed by the dissipation of Δψm at early-term period, blockage of cell transition into S phase, and considerable accumulation of cells in proapoptotic subG1 phase at prolonged incubation. Conclusion: The effect of the synergic cytotoxic activity of both agents allowed to suppose that photoexcited C60 fullerene promoted Cis-Pt accumulation in leukemic cells resistant to Cis-Pt. The data obtained could be useful for the development of new approaches to overcome drug-resistance of leukemic cells.

Proliferation inhibition of novel diphenylamine derivatives

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the world but some NSAIDs such as diclofenac and tolfenamic acid display levels of cytotoxicity, an effect which has been attributed to the presence of diphenylamine contained in their structures. A novel series of diphenylamine derivatives were synthetised and evaluated for their cytotoxic activities and proliferation inhibition. The most active compounds in the cytotoxicity tests were derivative 6g with an IC50 value of 2.5 ± 1.1 × 10−6 M and derivative 6f with an IC50 value of 6.0 ± 3.0 × 10−6 M (L1210 cell line) after 48 h incubation. The results demonstrate that leukemic L1210 cells were much more sensitive to compounds 6f and 6g than the HEK293T cells (IC50 = 35 × 10−6 M for 6f and IC50 > 50 × 10−6 M for 6g) and NIH-3T3 (IC50 > 50 × 10−6 M for both derivatives). The IC50 values show that these substances may selectively kill leukemic cells over non-cancer cells. Cell cycle analysis revealed that a primary trend of the diphenylamine derivatives was to arrest the cells in the G1-phase of the cell cycle within the first 24 h. UV–visible, fluorescence spectroscopy and circular dichroism were used in order to study the binding mode of the novel compounds with DNA. The binding constants determined by UV–visible spectroscopy were found to be in the range of 2.1–8.7 × 104 M−1. We suggest that the observed trend for binding constant K is likely to be a result of different binding thermodynamics accompanying the formation of the complexes.

Structure characterization and anti-leukemia activity of a novel polysaccharide from Angelica sinensis (Oliv.) Diels

A new water-soluble polysaccharide, APS-1II, with a molecular weight of 42.1 kDa was isolated from the roots of Angelica sinensis (Oliv.) Diels. APS-1II consists of arabinose (Ara), glucose (Glc) and fucose (Fuc) with a molar ratio of 2.48:1.05:1.00. The backbone of APS-1II is composed of 1,3-α-l-Araf and 1,6-α-d-Glcp with the branches containing 1,5-α-l-Araf, 1,4-β-d-Glcp, T-β-d-Glcp, 1,3-α-l-Fucp and T-α-l-Fucp. APS-1II inhibited the proliferation of human leukemia K562 and mouse L1210 cells in vitro and markedly prolonged the life span of L1210-bearing mice in vivo. APS-1II also increased the numbers of leukocytes and lymphocytes in peripheral blood, and significantly decreased plasma tumor necrosis factor, interleukin-2 and interferon-γ levels in L1210-bearing mice. Moreover, APS-1II administration concentration-dependently promoted the proliferation of the splenocytes, enhanced phagocytic activity of peritoneal macrophages and cytotoxicity of natural killer cells. These results suggest that APS-1II could effectively inhibit leukemia and induce a protective immune response, and it may be used as a suitable candidate reagent for leukemia therapy.

New Sesquiterpene Pyridine Alkaloids from Hippocratea excelsa

In total, three sesquiterpene pyridine alkaloids, including two new compounds and a triterpene, were isolated from the n-hexane extract of the stem barks of Hippocratea excelsa. The structures of these compounds were elucidated by spectroscopic methods. Pristimerin, a naturally occurring triterpenoid, exhibited cytotoxicity against L1210 cells.