Human Hepatoma Cancer Cells Research Articles

Novel Pd(ii)–salen complexes showing high in vitro anti-proliferative effects against human hepatoma cancer by modulating specific regulatory genes

We have reported the synthesis of a novel salen ligand and its mononuclear Pd-salen complexes derived from 2-{[2-hydroxy-3-{[(E)-(2-hydroxyphenyl)methylidene]amino}propyl)imino]methyl}phenol. The newly synthesized and isolated Pd(II) complexes have been identified and fully characterized by various physico-chemical studies viz., elemental analyses, IR, UV-Vis, (1)H, (13)C NMR spectroscopy, electron spray ionization mass spectrometry (ESI-MS) and TGA/DTA studies. The molecular structure of the salen ligand has been ascertained by single-crystal XRD and it is coordinated to Pd(II) ion through two nitrogen and two oxygen atoms. The UV-Vis data clearly suggest a square-planar environment around both the Pd(II) ions. The DNA binding studies of the synthesized compounds has been investigated by electron spectroscopy and fluorescence measurements. The results suggest that Pd(II) complexes bind to DNA strongly as compared to the free ligand. The free salen ligand and its Pd(II) complexes have also been tested against human hepatoma cancer cell line (Huh7) and results manifested exceptional anti-proliferative effects of the Pd(II) complexes. The anti-proliferative activity of Pd(II) complexes has been modulated by specific regulatory genes.

Biotransformation of bufadienolides by cell suspension cultures of Saussurea involucrata

The biotransformation of three bioactive bufadienolides, namely, bufotalin ( 1), telocinobufagin ( 2), and gamabufotalin ( 3) by cell suspension cultures of Saussurea involucrata yielded 11 products. Bufotalin yielded 3- epi-bufotalin ( 1a), 3- epi-desacetylbufotalin ( 1b), 3- epi-bufotalin 3- O-β- d-glucoside ( 1c), 1β-hydroxybufotalin ( 1d), and 5β-hydroxybufotalin ( 1e); telocinobufagin yielded 3-dehydroscillarenin ( 2a), 3-dehydrobufalin ( 2b), and 3- epi-telocinobufagin ( 2c); and gamabufotalin yielded 3- epi-gamabufotalin ( 3a), 3-dehydrogamabufotalin ( 3b), and 3-dehydro-Δ 1-gamabufotalin ( 3c), respectively. Among these 11 products, 1a, 1b, 1c, 1d, 3a and 3c are previously unreported. The structures of these metabolites were elucidated based on NMR spectroscopic analyses and mass spectrometry. Most metabolites showed significant cytotoxic activities against human hepatoma (HepG2) and breast cancer (MCF-7) cell lines. In addition, the time course for the biotransformation of 3 was investigated.

Penta‐1,2,3,4,6‐O‐galloyl‐beta‐D‐glucose induces senescence‐like terminal S‐phase arrest in human hepatoma and breast cancer cells

Senescence is a permanent growth arrest and has been implicated as an efficient anti-carcinogenesis mechanism. The purpose of this study was designed to test the hypothesis that penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a naturally occurring polyphonolic gallotannin compound, might induce this type of permanent growth arrest in cancer cells. Our results show, for the first time, that PGG-induced senescence-like S-phase arrest in HepG2, Huh-7 human hepatoma cells, and SKBr3 human breast cancer cells at sublethal doses, judged by cellular morphological changes, increased senescence-associated β-galactosidase (SA-β-gal) activity, together with loss of proliferative capacity after being released from the treatment. This senescence-like response was mediated by intracellular ROS generation, but was not attributed to p53 Ser15 phosphorylative activation and was uncoupled from the p21cip1 axis, which has been shown to mediate Pten loss-induced cellular senescence or oncogene-driven senescence. The findings of the present study implicate a novel mechanism of PGG action to induce an atypical cellular senescence, adding to its promise as a potential chemopreventive agent.

Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation

Hepatocellular carcinoma (HCC) is one of the most common solid cancers, representing the third cause of cancer-related death among cirrhotic patients. Treatment of advanced HCC has become a very active area of research. Perifosine, a new synthetic alkylphospholipid Akt inhibitor, has shown anti-tumor activity by inhibition of Akt phosphorylation. In this study, the effect of perifosine on the cell proliferation and apoptosis in hepatoma cells has been investigated. Cell growth inhibition was detected by MTT assay, cell cycle was analyzed by flow cytometry, AnnexinV-FITC apoptosis detection kit was used to detect cell apoptosis, and protein expression was examined by Western blotting analysis. Our present studies showed that Akt phosphorylation was inhibited by perifosine in HepG2 and Bel-7402 human hepatocellular carcinoma cells. Perifosine inhibited the growth of HepG2 cells and Bel-7402 cells in a dose-dependent manner, and arrested cell cycle progression at the G(2) phase. Apoptosis induction became more effective with increasing perifosine concentration. The caspase cascade and its downstream effectors, Poly (ADP-ribose) polymerase (PARP), were also activated simultaneously upon perifosine treatment. The proapoptotic effect of perifosine was in part depending on regulation of the phosphorylation level of ERK and JNK. Perifosine cotreatment substantially increased cytotoxic effects of cisplatin in HepG2 cells. Down-regulating the expression of Bcl-2 and up-regulating the level of Bax may be the potential mechanism for this synergistic effect. Our findings suggest that the small molecule Akt inhibitor perifosine shows substantial anti-tumor activity in human hepatoma cancer cell lines, and is a good candidate for treatment combinations with classical cytostatic compounds in hepatocellular carcinoma.

The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions

Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1α subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1α as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC50=5.16μM). The mechanism of this inhibition did not involve suppression of HIF-1α protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC50=4.75μM). Exposure of Huh7 cells to 10μΜ kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5–10μM) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.

A potent antitumor polysaccharide from the edible brown seaweedHydroclathrus clathratus

AbstractA sulfated polysaccharide H3-a1 [designated polysaccharide fraction, H3-a1, ofHydroclathrus clathratus(HCP)] was isolated and purified from an edible brown seaweedHydroclathrus clathratus; HCP contained about 8.6% protein and a relatively high sulfur content (8.2%). HCP significantly affected the growth of human acute promyelocytic leukemia cells (HL-60), human breast carcinoma (MCF-7) and human hepatocellular carcinoma cancer cell lines. As revealed by flow cytometry, when HCP was co-incubated with HL-60 and MCF-7 cells for 72 h, it induced significant sub-G1 arrest (apoptosis) of these cells. HCP caused G1 phase arrest but did not induce terminal differentiation of these cancer cells.In vivoantitumor tests showed that HCP inhibited tumor growth at doses of 20 and 50 mg kg-1in tumor-bearing BALB/c (supplied by the Laboratory Animal Services Centre of The Chinese University of Hong Kong) mice, but this effect was not due to anin vivoinhibitory effect on tumorigenesis. Nevertheless, HCP suppressed ascitic Sarcoma 180 tumor growth and prolonged the life span of the tumor-bearing mice by about 30–40%. HCP had no observed toxic side effects; it did not affect blood cells, or body, liver or spleen weights of mice 4, 7 and 10 days after treatment. This sulfated polysaccharide induced increased tumor necrosis factor-alpha (TNF-α) level in mouse serum. It also activated peritoneal macrophages to secrete TNF-α and nitric oxide.

Boswellic Acid Fractions Induces Apoptosis And Cell Cycle Arrest In Hepatocellular Carcinoma Cell Line (HEP-G2) Through P53 Accumulation

There has been growing interest in naturally occurring compounds with anti-cancer potential. Boswellic acid fractions (BA) are the bioactive constituent of the oleogum resin of Boswellia carterii Birdwood (Bursearceae). It has been shown to exert anti-neoplastic and anti-inflammatory effects. The antitumor activity molecular pathways of BA action are not clear. Nevertheless, BA is known to induce apoptosis by p53-dependent and p53-independent pathways in cancer cell lines. Growth inhibition is associated with induction of cellcycle arrest. In this study, the anticancer effect of BA in human HepG-2 cancercells line was investigated. BA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21. BA treatment triggered the apoptotic pathway indicated by a change in caspase-8 and caspase-3 activation. We also found that, BAinduced cell growth inhibition as a result of increase in the expression level of p53. These results confirm a critical role of p53 in BAinduced G2/M arrest and apoptosis of human hepatoma cancer cells.

Hepatoma Cell Growth Inhibition by Inducing Apoptosis with Polysaccharide Isolated from Turkey Tail Medicinal Mushroom, Trametes versicolor (L.: Fr.) Lloyd (Aphyllophoromycetideae)

The Trametes (=Coriolus) versicolor polysaccharide (CVP) is well known as an anti-tumor drug in clinical applications. Although recent studies have demonstrated that CVPs can inhibit the proliferation of cancer cells in vitro and in vivo, different purity levels of CVPs have a different affect on various cancer cells. In this study, crude CVPs were extracted and purified from T. versicolor dry fruit bodies by hot-water extraction, ethanol precipitation, and phenol-vitriolic colorimetry. The in vitro cytotoxic activities of CVPs were examined on the human hepatoma cancer (QGY) cell lines by using an MTT assay. The cell cycle and cell death (apoptosis) of QGY cells were investigated by flow cytometry. The expression of genes involved in the apoptosis process, such as p53, Bcl-2, and Fas, was also studied using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. These results showed that CVPs inhibited the proliferation of QGY in low concentrations (<20 mg/L) and the IC50 value was 4.25 mg/L. Changes that are characteristic of apoptosis, such as a found trapezoidal belt with DNA, were observed in the QGY cells treated with CVPs. There was a significant decrease in the expression of the cell cycle-related genes (p53, Bcl-2, and Fas,) in these cells following treatment with CVPs. These results thus indicate that CVPs can be a potential candidate to ameliorate toxic effects when used in cancer therapy.

Phorbaketals A, B, and C, Sesterterpenoids with a Spiroketal of Hydrobenzopyran Moiety Isolated from the Marine Sponge Phorbas sp.

Three new sesterterpenoids, phorbaketals A (1), B (2), and C (3) which have a spiroketal of the hydrobenzopyran moiety, were isolated from the Korean marine sponge Phorbas sp. Their complete structures were elucidated by spectral and chemical methods. They exhibited moderate cytotoxicity against human colorectal, hepatoma, and lung cancer cell lines. Furthermore, the cultivation of the bacterial fraction from the sponge afforded compound 1.

Lipid‐Soluble Extracts as the Main Source of Anticancer Activity in Ginseng and Ginseng Marc

AbstractThe anticancer activity of ginseng originated mainly from lipid‐soluble components. The hexane extract of ginseng marc (HEGM) showed a potent inhibitory activity on human hepatoma (HepG2, GI50 = 41.7 μg/ml) and breast (MCF‐7, GI50 = 54.4 μg/ml) cancer cell proliferation in vitro in a concentration‐dependent manner as did the hexane extract of ginseng (HEG), with GI50 values of 21.1 μg/ml in HepG2 and 41.2 μg/ml in MCF‐7. The water extract of ginseng (WEG) possessed a low anticancer activity against both cancer cell lines, but the hexane‐soluble fraction of WEG (HSF/WEG) showed a potent anticancer activity against HepG2 (GI50 = 38.7 μg/ml) and MCF‐7 cells (GI50 = 51.1 μg/ml). The hexane extraction in ginseng was a very promising protocol for the maximum recovery of the anticancer active components in high concentrations. Also the adoption of hexane extraction after water extraction of ginseng was successful in the effective utilization of the residual lipid‐soluble anticancer active components in ginseng marc.

Butein induces G 2/M phase arrest and apoptosis in human hepatoma cancer cells through ROS generation

We investigated the molecular effects of 3,4,2′,4′-tetrahydroxychalcone (butein) treatment in two human hepatoma cancer cell lines–HepG2 and Hep3B. Butein treatment inhibited cancer cell growth by inducing G 2/M phase arrest and apoptosis. Butein-induced G 2/M phase arrest was associated with increased ATM, Chk1, and Chk2 phosphorylations and reduced cdc25C levels. Additionally, butein treatment enhanced inactivated phospho-Cdc2 levels, reduced Cdc2 kinase activity, and generated reactive oxygen species (ROS) that was accompanied by JNK activation. The extent of butein-induced G 2/M phase arrest significantly decreased following pretreatment with N-acetyl- l-cysteine or glutathione and following JNK phosphorylation reduction by SP600125. Both N-acetyl- l-cysteine and glutathione also decreased butein-mediated apoptosis. Taken together, these results imply a critical role of ROS and JNK in the anticancer effects of butein.

An alternative sequential extraction process for maximal utilization of bioactive components from Korean red ginseng

Two types of sequential extraction process (SEP) for the recovery of bioactive components from Korean red ginseng were examined. As a SEP (normal SEP, nSEP), Korean red ginseng was sequentially treated using hot water and n-hexane for the successive extraction of water-soluble and lipid-soluble components. Also by changing the sequential order of solvents, an alternative SEP (reverse SEP, rSEP) in which n-hexane extraction was followed by hot water extraction, was proposed. Regardless of the sequential order of solvents, the recovery yield of acidic polysaccharide (AP) and crude saponin (CS) showed no significant change. On the other hand, in the rSEP, the lipid-soluble fraction was obtained from red ginseng with an enhanced recovery yield, four times higher than that in nSEP. Additionally, from dose-response assays to assess the effects of lipid-soluble components on the proliferation of human hepatoma (HepG2) and breast (MCF-7) cancer cell lines, it was found that hexane extract of red ginseng (HER) in rSEP has higher efficacy than the hexane extract of red ginseng marc (HERM) obtained in nSEP. This strongly suggested that rSEP would be a more attractive industrial process in terms of the efficacy of lipid-soluble extract as well as the recovery yield.

CXCR4 Regulates the Early Extravasation of Metastatic Tumor Cells In Vivo

Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% ± 4.3% vs anti-CXCR4: 6.0% ± 5.0%, P < .001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.

Lignan constituents from Chloranthus japonicus Sieb.

A new coumarinolignan glucoside named yinxiancaoside C, along with five known benzofuran lignans, have been isolated from the whole plant of Chloranthus japonicus Sieb. The structures of compounds 1-6 were elucidated by chemical and spectroscopic methods including 1D-NMR, 2D-NMR, ESI-MS and HR-ESI-MS. Five known benzofuran lignans were firstly discovered in the Chloranthaceae. In addition, the cytotoxic activity of the isolated compounds against human hepatoma (Hepg-2), ovarian carcinoma (OV420), and breast cancer (MCF-7) cells was investigated by MTT method.

Silibinin inhibits hypoxia-inducible factor-1α and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy

The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1alpha protein degradation rate nor HIF-1alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1alpha accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1alpha expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.

Cytotoxic activities of diarylheptanoids from Alnus japonica

The diarylheptanoids (1-10) 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-beta-D-glucopyranosyl(1-->3)-beta-D-xylopyranoside (1), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-beta-D-apiofuranosyl(1-->6)-beta-D-glucopyranoside (2), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-beta-D-glucopyranoside (3), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane (4), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-beta-D-glucopyranoside (5), oregonin (6), hirsutanonol (7), hirsutenone (8), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-O-beta-D-xylopyranoside (9), and platyphylloside (10), isolated from the bark of Alnus japonica, were analyzed for their cytotoxic activities on various human and mouse cancer cell lines. The cytotoxic activities of these ten compounds were evaluated against murine B16 melanoma, human SNU-1 gastric cancer, human SNU-354 hepatoma cancer and human SNU-C4 colorectal cell lines. The diarylheptanoids showed potent cytotoxic activities against murine B16 melanoma cells and human SNU-C1 gastric cancer cell when the cell viability was analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay.

Mono-tetrahydrofuran annonaceous acetogenins from Annona squamosa as cytotoxic agents and calcium ion chelators

Eight new mono-tetrahydrofuran (THF)-type annonaceous acetogenins, squafosacins B, C, F, and G (1-4), squadiolins A-C (5-7), and cis-annotemoyin-1 (8), as well as eight known annonaceous acetogenins, glabranin, annotemoyins-1 and -2, bullatencin, cis-bullatencin, and uvariamicins-I, -II, and -III, were isolated from the seeds of Annona squamosa by HPLC. The structures of all new isolates were elucidated by using spectroscopic and chemical methods. Squadiolins A (5) and B (6) showed ng/mL potency against human Hep G2 hepatoma cells and significant cytotoxic activity against human MDA-MB-231 breast cancer cells. Squafosacin B (1) also exhibited significant cytotoxic activity against human Hep G2 and 3B hepatoma and MCF-7 breast cancer cells. In addition, the chelation of mono-THF acetogenins with calcium ions was investigated using isothermal titration calorimetry.

Mono-tetrahydrofuran Annonaceous Acetogenins from Annona squamosa as Cytotoxic Agents and Calcium Ion Chelators

Eight new mono-tetrahydrofuran (THF)-type annonaceous acetogenins, squafosacins B, C, F, and G (1-4), squadiolins A-C (5-7), and cis-annotemoyin-1 (8), as well as eight known annonaceous acetogenins, glabranin, annotemoyins-1 and -2, bullatencin, cis-bullatencin, and uvariamicins-I, -II, and -III, were isolated from the seeds of Annona squamosa by HPLC. The structures of all new isolates were elucidated by using spectroscopic and chemical methods. Squadiolins A (5) and B (6) showed ng/mL potency against human Hep G2 hepatoma cells and significant cytotoxic activity against human MDA-MB-231 breast cancer cells. Squafosacin B (1) also exhibited significant cytotoxic activity against human Hep G2 and 3B hepatoma and MCF-7 breast cancer cells. In addition, the chelation of mono-THF acetogenins with calcium ions was investigated using isothermal titration calorimetry.

Cytotoxic Triterpenoids from the Root Bark of Helicteres angustifolia

Three new triterpenoids, 3beta-acetoxy-27-[(E)-cinnamoyloxy]lup-20(29)-en-28-oic acid methyl ester (1), 3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]lup-20(29)-en-28-oic acid (2), and 3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]olean-12-en-28-oic acid methyl ester (3), together with nine known triterpenoids, 4-12, were isolated from the root bark of Helicteres angustifolia. The structures of these compounds were established on the basis of spectroscopic methods including 2D-NMR experiments. All twelve compounds were tested for their cytotoxic activities against human colorectal cancer (COLO 205), human hepatoma (Hep G2), and human gastric cancer (AGS) cell lines in vitro. Among them, compounds 2, 3, 3beta-O-[(E)-coumaroyl]betulinic acid (6), and pyracrenic acid (7) showed significant cytotoxic activities against human cancer cells COLO 205 and AGS.

Functional characterization of interleukin-15 gene transduction into the human natural killer cell line NKL

Genetic modification of natural killer (NK) cells is a potential approach to gene-based immunotherapy of cancer. We created human interleukin-15 (hIL-15) gene-modified NKL cells and investigated their functional characterization in vitro. A recombinant vector (pcDNA3-IL15) or control vector (pcDNA3) was transferred into NKL cells by an electroporation method. Standard reverse transcriptase-polymerase chain reaction (RT-PCR), flow cytometry and MTT methods were performed for NK cell proliferation, apoptosis, cytotoxicity assays and gene expression tests. Compared with parental NKL cells, hIL-15 gene modification promoted NK cell proliferation at low doses of IL-2 and inhibited cell apoptosis, which was associated with the up-regulation of anti-apoptosis genes Bcl-2, Bcl-xl and Mcl-1 as well as the down-regulation of apoptosis genes Bim and Noxa. Moreover, the anti-tumor activity of hIL-15 gene-transduced NKL cells against human hepatoma cancer cell line HepG2, H7402 and PLC/PRF-5 cells was enhanced, at least partly, through increasing expression of cytotoxicity-associated genes, including interferon (IFN)-gamma, perforin and FasL. The hIL-15 genetic modification could improve the proliferation, anti-apoptosis and natural cytotoxicity of NKL cells against hepatocarcinoma cells. These data suggest that hIL-15 gene-modified NKL cells could be useful for clinical cancer immunotherapy in the future.