Highest Anti-proliferation Activity Research Articles

Examination of in vitro and in vivo antitumor activity of PARP1 selective inhibitor D0112-005.

e15115 Background: The approved PARP inhibitors have demonstrated efficacy in ovarian, breast, prostate, and pancreatic cancers, particularly in homologous recombination repair (HRR)-deficient tumors, including BRCA mutant tumors. The severe hematological toxicity of first-generation PARPi in combination with chemotherapy is due to the lack of selectivity for PARP2. So, we developed selective PARP1 inhibitor D0112-005 with the aim to improve safety and efficacy. Methods: The selectivity of D0112-005 on PARP1, PARP2 was measured by chemiluminescent assay kit and PARP trap™ assay kit. The anti-proliferative ability of D0112-005 was evaluated by CCK-8 in BRCA mutant cell lines. In vivo anti-tumor effect of D0112-005 was evaluated in MDA-MB-436 BRCA1 mutant xenograft model. The potential for hematologic toxicity was evaluated in rats for 28 days repeat-dose and dogs for 14 days repeat-dose. Results: D0112-005 is a highly potent and selective inhibitor of PARP1 with 2000-fold selectivity for PARP1 over PARP2 and PARP3. D0112-005 trapped PARP1-DNA with an EC50 value of 6.49 nM. In contrast, the EC50 of PARP2-DNA trapping was 430μM. These data demonstrate that D0112-005 is a potent and selective PARP1 trapper. D0112-005 showed high anti-proliferation activity against BRCA mutant MDA-MB-436 and HCC1395 cell lines, with IC50 values of 2.06 nM and 2.446 nM, respectively. In the MDA-MB-436 BRCA1m xenograft model, a dose-dependent anti-tumor effect was observed after 21 days administration, with TGIs of 38.77%, 106.7% and 111.73% at the dose of 0.1, 0.3 or 1 mg/kg once daily by oral, respectively. In the 1 mg/kg group, the anti-tumor efficacy was maintained after 14 days of drug withdrawal. D0112-005 showed well tolerance without bodyweight loss. In rat 28 days repeat dose study, D0112-005 100mg/kg had less changes on hematologic parameters compared with Olaparib. The main toxic reaction of D0112-005 (10mg/kg) was reversible thrombocytopenia in dog 14 days repeated toxicity study. Conclusions: D0112-005 potently and selectively inhibits PARP1 resulting in excellent anti-tumor activity in vivo and in vitro, which also good safety profile in the repeated toxicity study in rats and dogs.

Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

Conformationally constrained potent inhibitors for enhancer of zeste homolog 2 (EZH2)

The enhancer of zeste homolog 2 (EZH2) plays the role of the main catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes the methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been observed in many types of hematologic malignancies and solid tumors, such as myeloma, lymphoma, prostate, breast, kidney, and lung cancers. EZH2 has been demonstrated as a promising therapeutic target for the treatment of tumors. Based on the structure of 1 (EPZ-6438), a series of novel conformationally constrained derivatives were designed and synthesized aiming to improve the EZH2 inhibition activity, especially for mutated EZH2. Structure and activity relationship (SAR) exploration and optimization at both enzymatic and cellular levels led to the discovery of 28. In vitro, 28 displayed potent EZH2 inhibition activity with an IC50 value of 0.95 nM, which is comparable to EPZ-6438 (1). 28 exhibited high anti-proliferation activity against different lymphoma cell lines including WSU-DLCL2, Pfeiffer and Karpas-422 (IC50 = 2.36, 1.73, and 1.82 nM, respectively). In vivo, 28 showed acceptable pharmacokinetic characteristics (oral bioavailability F = 36.9%) and better efficacy than 1 in both Pfeiffer and Karpas-422 xenograft mouse models, suggesting that it can be further developed as a potential therapeutic candidate for EZH2-associated cancers.

Erlotinib-Loaded Dendrimer Nanocomposites as a Targeted Lung Cancer Chemotherapy.

Lung cancer is the main cause of cancer-related mortality globally. Erlotinib is a tyrosine kinase inhibitor, affecting both cancerous cell proliferation and survival. The emergence of oncological nanotechnology has provided a novel drug delivery system for erlotinib. The aims of this current investigation were to formulate two different polyamidoamine (PAMAM) dendrimer generations-generation 4 (G4) and generation 5 (G5) PAMAM dendrimer-to study the impact of two different PAMAM dendrimer formulations on entrapment by drug loading and encapsulation efficiency tests; to assess various characterizations, including particle size distribution, polydispersity index, and zeta potential; and to evaluate in vitro drug release along with assessing in situ human lung adenocarcinoma cell culture. The results showed that the average particle size of G4 and G5 nanocomposites were 200 nm and 224.8 nm, with polydispersity index values of 0.05 and 0.300, zeta potential values of 11.54 and 4.26 mV of G4 and G5 PAMAM dendrimer, respectively. Comparative in situ study showed that cationic G4 erlotinib-loaded dendrimer was more selective and had higher antiproliferation activity against A549 lung cells compared to neutral G5 erlotinib-loaded dendrimers and erlotinib alone. These conclusions highlight the potential effect of cationic G4 dendrimer as a targeting-sustained-release carrier for erlotinib.

Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics.

Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,β-unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

Aktivitas Antiproliferasi Ekstrak Etanol Biji Kopi Hijau Robusta Lampung pada Sel Lestari Tumor Anjing

This study aim at determining the activity of ethanol extract of Robusta green coffee beans as an antiproliferation agent in MCA-B1, MCM-B2, and Vero normal cell lines as a control. Ethanol extract of Robusta green coffee beans was obtained by maceration method, bioactive compounds in the extract were tested by phytochemical screening methods, testing levels of antioxidants were tested by 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, cytotoxicity effects (LC50) were tested by the method Brine Shrimp Lethallity Test (BSLT) and antiproliferation activity were carried out by counting the number of cells after being tested with several extract concentrations namely 100, 250, 400, 550, 700 and 850 ppm and doxorubicin as a positive control with a concentration of 100 ppm. The results showed that the ethanol extract of Robusta green coffee beans contained flavonoids and tannins, had very strong antioxidant levels with IC50 values of 40.9923 ppm, cytotoxicity effects obtained LC50 values of 430.64 ppm, and the highest antiproliferation activity was achieved at a concentration of 850 ppm at 69.58 % in MCM-B2 tumor cells, 60.46% in MCA-B1 tumor cells, and 14.2% in Vero normal cells. Based on the results, the ethanol extract of Robusta Lampung green coffee beans has antiproliferation activity on the test tumor cells and is relatively non-toxic to normal cells.

Abstract 4177: Preclinical development of ABM-1310, a novel BRAF Inhibitor to treat cancer with brain metastasis

Abstract BRAF is a key molecule activated by RAS in the MAPK pathway that mainly controls cell proliferation. BRAF mutation is detected in about 8% of all cancer population, and more than 50% is BRAFv600e, which causes constitutive MAPK activation. BRAFv600 mutation is found in various cancers such as melanoma, colorectal cancer, glioma, lung cancer, thyroid cancer, pancreatic cancer, ovary cancer etc. ABM-1310 is a novel small molecule BRAF inhibitor that specific inhibits BRAFv600 mutant form with high water solubility, cell permeability, and blood brain barrier (BBB) penetration. Although current target or immune-therapies are reported with some variable effects, melanoma with brain metastasis is still a significant challenge in clinic. With high BBB penetration and high exposure in brain, ABM-1310 has good potential to treat tumors bearing BRAFv600 mutation with brain metastasis. In-vitro data shown similar on-target enzyme activity of ABM-1310 to marketed BRAF inhibitors on BRAFv600e, as well as high anti-proliferation activity in multiple cancer cell lines with BRAF V600E mutation like A375, Colo-829, and HT-29 etc. In vivo pharmacology studies demonstrated that ABM-1310 had good potency of tumor growth inhibition with oral dose as low as 1mg/kg/day. ABM-1310 treatment also improved animal overall survival in several cell-line derived xenograft (CDX) models, including subcutaneous, intracranial and intracardiac melanoma models. Non-clinical pharmacokinetics studies also shown ABM-1310 had a favorable ADME profile both in vitro and in vivo in animals. ABM-1310 demonstrated excellent brain penetration in animals. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs all revealed that ABM-1310 had a good safety profile with NOAEL of 100mg/kg/day in SD rats and 30mg/kg/day in beagle dogs. Based on these supportive preclinical study results, IND of ABM-1310 was submitted in 2019 Q4 to investigate its safety in humans as signal reagent, which will be followed by further clinic development of ABM-1310, or combination with other molecules to treat cancers with BRAFv600 mutation, especially with brain metastasis. Citation Format: Yong Hu, Chen Chen, Charles Huang, Min Xu, Youqin Chen, Xiyuan Chen, Li Zhao. Preclinical development of ABM-1310, a novel BRAF Inhibitor to treat cancer with brain metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4177.

Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy.

BackgroundHuman epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy.MethodsTZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake.ResultsThe G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer.ConclusionIn the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.

Evaluation of biochemical constituents and inhibitory effect of tea clone 100 on colorectal cancer cell line HCT- 116

Purpose: To evaluate the total content of polyphenols and the free radical scavenging activity of three different extracts of three types of tea clone 100 (black, green and white), and their anti-proliferative effects on colorectal cancer.Methods: Five major polyphenols, viz, (+)-catechin, (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin gallate and (-)-epigallocatechin gallate, were identified using thin layer chromatography (TLC). Catechins were quantified by high performance liquid chromatography (HPLC). Antioxidant activity was measured by DPPH radical scavenging method, while 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) assay was employed for the determination of cell viability of colon cell line HCT-116 after 24 and 48 h.Results: The aqueous methanol (70 %) extract of white tea yielded the highest amount of polyphenols (36.67 ± 0.54 mg GAE/g dry weight). The DPPH radical scavenging activity of white tea was 71.74 ± 0.42 %, and it produced high anti-proliferation activity against colorectal cancer cell line HCT-116 (86.06 ± 0.54 %).Conclusion: White tea extract possesses high DPPH radical scavenging activity, and exerts good antiproliferative effects against colorectal cancer cell line HCT-116, most likely due to its catechin content.Keywords: Camellia sinensis L., Catechin, DPPH radical scavenging, Anti-cancer

Synthesis of Nano Sulfur Particles and their Antitumor Activity

Objectives: The present study is designed to evaluate the antitumor activity of sulphur containing compounds in Nano formulations against Ehrlisch Ascites Carcinoma (EAC) in female albino mice. Methods: Preparation of sulfur nanoparticles (S-NPs) was done throughout. Firstly, the evaluation of their composition and purity by fourier transform infrared spectrometer (FT-IR) analysis. Secondly, the shape and size of S-NPs were investigated by scanning electron microscopy (SEM) techniques in all S-NPs samples which were prepared with Tetramethylammoniumbromide (TMAB) surfactant, Then, Energy-dispersive X-ray spectroscopy (EDS) for the evaluation of their composition and purity, after that the X-Ray diffraction patterns were measured for prepared S-NPs with TMAB surfactant, and the determination of S-NPs antitumor activity against (breast carcinoma cell line (MCF7), liver carcinoma cell line (HEPG2), colon carcinoma cell line (HCT116), prostatic carcinoma cell line (PC3). Finally, determination biochemical assay of S-NPs by using female mice bearing EAC and of the assessment of liver functions and evaluation of kidney functions and determination of some heart functions in serum and hematology markers. Results: This study revealed that S-NPs showed high strong activities in concentration (5 mg/kg) as it improvement of liver functions production compared to the positive control group, also showed the effect of S-NPs of the kidney functions, heart functions and hematology parameters in all studied groups and a significant increase in activities compared with positive control group. Conclusion: S-NPs play an important role in improving liver functions, kidney functions and the heart functions of resulted in significantly increase activity against tumour and plays an important role in improving oxidative stress resulted in high antiproliferation activity against (MCF-7, HepG2, HCT116 and PC3) cell lines, and significantly increase with S-NPs reduced most of the hematological parameters towards the best compared to the positive control group.

Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo

In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors.The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line.Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer.

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer.

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

Biochemical and phytochemical studies on Balanities aegyptiaca fruits

Objectives: Phytochemical screeninig of Balanities aegyptiaca (B.a.) extract and invitro determination of some biochemical effects. Methods: preparation of defatted Balanities aegyptiaca total extract, it's characterization was done throughout Firstly, quantitative and qualitative determination of active phenolic components by HPLC and spectrophotometer analysis. Secondly, identification of different function groups by IR analysis and surface elements by electronic microscope, then estimation for saponins content by spectrophotometer, After that estimation of total flavonoids, carbohydrates and proteins. Finally, determination of B. a. extract antioxidant activity by using DPPH, anti-inflammatory activity and antitumor activity using (MCF-7) human breast adenocarcinoma cell line. Results: This study revealed that total extract of Balanities fruits showed high levels of antioxidants as each 1 gram contained 10 mg of ascorbic acid and anti-inflammatory activities as it inhibited NO production by 60% compared to positive control group. Also, it revealed high antiproliferation activity IC50=21.2 ug/ml correlated with its phytochemical screening which showed the presence of high levels of phenolics, flavnoids, minerals (Zn, Mg, Ca, K, Na, Fe, Cl, Al, Si, O and Carbon) and Saponins. Conclusion: Balanities aegyptiaca extract plays an important role in improving oxidative stress resulted in high antiproliferation activity against (MCF-7) and posses a strong anti-inflammatory agent, Furthermore purification and isolation of active compounds will help in recommendation of new antinflammatory and antitumor herbal treatments.

Inhibition of angiogenesis and metastasis of uveal melanoma cells by astragaloside IV

Astragaloside IV (AS) has been recently shown to possess pharmacologic activities against cancer. Vascular endothelial growth factor (VEGF) plays a prominent role in the induction of physiological or pathophysiological processes of tumor angiogenesis. The present study focuses on the anti-angiogenesis effects of AS in uveal melanoma cells. In this study, AS was demonstrated to exhibit higher anti-proliferation activity against cultured uveal melanoma cells compared with control. AS was also found to inhibit VEGF-a expression and secretion in human cells; functional assays also indicated inhibition of invasion and migration of the cells. This provides new information on a significant anti-tumor effect of AS. This saponin may be used as a novel therapeutic drug for the inhibition of tumor angiogenesis and metastasis. Key words: Astragaloside IV, anti-cancer, vascular endothelial growth factor, uveal melanoma.

2′‐Chloro‐4′‐aminoflavone Derivatives Selectively Targeting Hepatocarcinoma Cells: Convenient Synthetic Process, G2/M Cell Cycle Arrest and Apoptosis Triggers

A series of 2'-chloro-4'-nitroflavone and 2'-chloro-4'-aminoflavone derivatives were synthesized by a convenient synthetic process. The in vitro anti-proliferation ability of these compounds was evaluated against hepatocarcinoma cells (HepG2), breast adenocarcinoma cells (MCF-7), and human chronic myelogenous leukemia cells (K562). Most of synthetic compounds possessed notable anti-proliferation activity against HepG2 cells and little activity against MCF-7 cells and K562 cells. In particular, compounds 4c and 4e exhibited high anti-proliferation activity against HepG2 cells with IC(50) at about 2.0 µM. Further toxicity screening toward normal human hepatocytes indicated that some compounds had low toxicity against normal liver cells, among which 4e displayed very weak effects on QSG7701 and HL7702 cells, with IC(50) values >100 and 50 µM, respectively. Compound 4c, with the best anti-proliferation activity in amino-substituted flavones (IC(50) = 2.0 µM), was selected for further evaluation of its effects on apoptosis and the cell cycle. HepG2 cells were exposed to this compound at 10 µM, which induced nuclear disassembly and DNA fragmentation. Flow cytometry analysis suggested that the population of apoptotic cells greatly increased in the 4c-treated HepG2 cells, and the cell cycle was arrested at the G(2)/M phase.

Purification, characterization and anti-proliferation activity of polysaccharides from Flammulina velutipes

Abstract A polysaccharide was isolated from Flammulina velutipes (FVP) using ultrasonic-assisted extraction, and then further purified by DEAE cellulose-52 chromatography and Sephadex G-100 size-exclusion chromatography to afford FVP-1 and FVP-2. Structural characteristics of FVP-1 and FVP-2 (including molecular weight, monosaccharides composition, sulfate and uronic acid contents, triple helical structures, ultraviolet spectrum, and infrared spectrum) were investigated, and their anti-proliferation activities against human gastric cancer BGC-823 cells and lung cancer A549 cells were researched in vitro . Results suggested that both FVP-1 and FVP-2 could significantly suppress the proliferation of BGC-823 cells in a concentration-dependent manner. The highest inhibitory rates were 78% for FVP-1 and 95% for FVP-2 at the concentration of 200 μg/ml, respectively. This high anti-proliferation activity was inferred to be owing to the structural characterizations of polysaccharide, and the recognition of biological system for the triple helical structures of polysaccharides.

Efficient activation of p53 pathway in A549 cells exposed to L2, a novel compound targeting p53–MDM2 interaction

The tumor suppressor p53 plays a key role in the regulation of cell cycle, apoptosis, DNA repair, and senescence. It acts as a transcriptional factor, and is able to activate various genes to exert specific functions. MDM2, the main regulator of p53, inhibits the function of p53 through direct interaction. On the basis of this finding, inhibiting the MDM2-p53 interaction can be a potentially important target for cancer therapy. We showed here that L2, an analog of small-molecule MDM2 antagonist nutlins, stabilized p53 and selectively activated the p53 pathway in p53 wild-type A549 cells, resulting in a pronounced antiproliferation effect through inducing cell cycle arrest and apoptosis. Meanwhile, we confirmed by immunoprecipitation analysis that L2 could also inhibit MDM2-p53 interaction, similar to nutlin-1. Real-time PCR results revealed that L2 had no effect on the p53 gene transcriptional level, but it could induce the upregulation of p21 at the transcriptional level, which was the downstream of p53. Therefore, we concluded that the accumulation of p53 caused by L2 was mainly because of the decrease of the protein degradation rather than the elevation of p53 gene expression. Furthermore, no phosphor-p53 formed after L2 treatments, indicating that a genetoxic mechanism was unlikely to contribute to the activation of p53 by L2. In conclusion, the data acquired from A549 cells indicated that L2 exhibited high antiproliferation activity by disrupting MDM2-p53 interaction, and that the mechanism was derived from the activation of p53 and the p53 pathway. It was also surprising that L2 showed high antiproliferation effect against p53 null HL60 cells, which was quite different from nutlin-1. G2/M phase arrest might have contributed to the high antiproliferation activity of L2 on HL60 cells. The changes of p53 and MDM2 protein levels in L2-treated HL60 cells indicated that the mechanisms involved in the cell cycle arrest in A549 and HL60 cells were probably different, to which our future research would be devoted.