melitten and Breast-Neoplasms

While the survival rate has increased due to treatments for breast cancer, the quality of life has decreased because of the side effects of chemotherapy. Various toxins are being developed as alternative breast cancer treatments, and bee venom is drawing attention as one of them. We analyzed the effect of bee venom and its components on breast cancer cells and reviewed the mechanism underlying the anticancer effects of bee venom. Data up to March 2022 were searched from PubMed, EMBASE, OASIS, KISS, and Science Direct online databases, and studies that met the inclusion criteria were reviewed. Among 612 studies, 11 were selected for this research. Diverse drugs were administered, including crude bee venom, melittin, phospholipase A2, and their complexes. All drugs reduced the number of breast cancer cells in proportion to the dose and time. The mechanisms of anticancer effects included cytotoxicity, apoptosis, cell targeting, gene expression regulation, and cell lysis. Summarily, bee venom and its components exert anticancer effects on human breast cancer cells. Depending on the mechanisms of anticancer effects, side effects are expected to be reduced by using various vehicles. Bee venom and its components have the potential to prevent and treat breast cancer in the future.

Topics: Apoptosis; Bee Venoms; Breast Neoplasms; Female; Humans; Melitten; Quality of Life

A targeted treatment that effectively destroys human breast, prostate, ovarian, and testicular cancer cells that express luteinizing hormone/chorionic gonadotropin (LH/CG) receptors has been developed. The treatment consists of a conjugate of a membrane-disrupting lytic peptide (Hecate, Phor14, or Phor21) and a 15-amino acid segment of the beta chain of CG. Because these conjugates act primarily by destroying cell membranes, their effects are independent of cell proliferation. The conjugates are relatively small molecules, are rapidly metabolized, and are not antigenic. In a series of independent experiments conducted in three different laboratories, the validity of the concept has been established, and it has been shown that the LH/CG receptor capacity of the cancer cells is directly related to the sensitivity of the lytic peptide conjugates. Sensitivity to the drugs can be increased by pretreating prostate or breast cancer cells with FSH or estradiol to up-regulate LH/CG receptors. A series of 23 in vivo experiments involving a total of 1630 nude mice bearing xenografts of human prostate or breast cancer cells showed convincingly that all three lytic peptide-betaCG compounds were highly effective in destroying tumors and reducing tumor burden. Hecate-betaCG was less effective in mice bearing ovarian epithelial cancer cell xenografts, but was highly effective in treating granulosa cell tumors in transgenic mice. In addition, Hecate-betaCG and Phor14-betaCG were highly effective in targeting and destroying prostate and breast cancer cell metastases in the presence or absence of the primary tumors. Although effective in vitro, neither Hecate nor Phor14 alone were effective in reducing primary tumor volume or burden in nude mice bearing prostate or breast cancer xenografts.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Membrane; Chorionic Gonadotropin, beta Subunit, Human; Drug Screening Assays, Antitumor; Female; Humans; Male; Melitten; Peptides; Prostatic Neoplasms; Receptors, LH; Testicular Neoplasms

Natural killer (NK) cells exert cytotoxic effects against infected or stressed cells, such as tumor cells, without the limitation of major histocompatibility complex (MHC) I. NK cells secrete perforins to form tunnels to mediate the entry of granzyme into target cells. This strategy, selected by natural evolution, provides a feasible method for the delivery of antitumor drugs against intracellular targets, and avoids drug-resistant mechanisms in tumor cells, such as the pumping out of drugs mediated by multidrug resistance. We constructed pH-labile artificial NK cells (ANKC) based on nature to mediate high levels of drugs in tumor cells to overcome tumor drug resistance. Mesoporous silicon nanoparticles (MSNs) modified with benzaldehyde were designed to function as scaffolds for ANKC. Doxorubicin (Dox), a model antitumor drug, was loaded into the pores of MSNs. Melittin, a pore-forming peptide, was utilized as the gate for mesopores with an acid-labile Schiff base linkage. pH-labile ANKC released melittin and Dox in slightly acidic tumor microenvironments. Melittin, like perforin, assembled tunnels on the plasma membrane or endosome, ensuring the intracellular transportation of Dox. Dox, similar to granzyme, induced the apoptosis of tumor cells. The combinational treatment partially eased the drug resistance mechanism, such as pumping out of drugs, by continuous intracellular drug accumulation mediated by melittin pores. The pH-labile ANKC demonstrated significant Dox enrichment in drug-resistant MCF-7/Adr cells and MCF-7/Adr-based xenograft tumors in a mouse model, which eventually contributed to efficient inhibition of the proliferation and growth of MCF-7/Adr tumors. PH-labile ANKC provided a potential strategy to treat drug-resistant tumors.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; Female; Granzymes; Humans; Hydrogen-Ion Concentration; Killer Cells, Natural; MCF-7 Cells; Melitten; Mice; Nanoparticles; Tumor Microenvironment

A novel polyelectrolyte nanocarrier was synthesized via layer-by-layer self-assembly of polycationic and polyanionic chains. The nanocarrier is composed of polyglutamate grafted chitosan core, dextran sulfate as a complexing agent, and polyethyleneimine shell decorated with folic acid. This polyelectrolyte complex has unique physicochemical properties so that the core is considered as an efficient carrier for LTX-315 and melittin peptides, and the shell is suitable for delivery of miR-34a. The spherical nanocarriers with an average size of 123 ± 5 nm and a zeta potential of -36 ± 1 mV demonstrated controlled-release of gene and peptides ensured a synergistic effect in establishing multiple cell death pathways on chemoresistance human breast adenocarcinoma cell line, MDA-MB-231. In vitro cell viability assays also revealed no cytotoxicity for the nanocarriers, and an IC50 of 15 μg/mL and 150 μg/mL for melittin and LTX-315, respectively, after 48 h, whereas co-delivery of melittin with miR-34a increased smart death induction by 54%.

Topics: Breast Neoplasms; Cell Death; Cell Line, Tumor; Chitosan; Female; Humans; Melitten; MicroRNAs; Nanoparticles; Oligopeptides; Polyelectrolytes

Breast cancer is the most common case of cancers. Apitheraphy has been traditionally used for abundance diseases. This study aims to evaluate and compare the anti-breast cancer activity of melittin from Indonesia's Apic cerana as a potential drug for treating breast cancer.. Apis cerana bee venom (BV) was collected from a bee farm in Cikurutung, Bandung using an electrical venom device. The BV was then purified using the ÄKTA Start system and HiTrap™ SP HP cation exchange chromatography column. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to identify melittin based on its molecular mass and lowry's protein assay to measure melittin concentration. Melittin cytotoxicity was measured with brine shrimp lethality test (BSLT), while MCF-7 breast cancer cells MTT assay was used to measure its anti-breast cancer activity, based on inhinition rate.. 95.432 μg/mL melittin is purified from 62.8 mg/L BV, using  cation exchange chromatography. Melittin in vitro analysis with MCF-7 MTT assay is used to determine anti-breast cancer activity in dose dependent manner. Furthermore, melttin BSLT result showed a LC50 16.67675 μg/mL. Therefore, the MTT assay  was conducted in 5, 10 and 15 μg/mL with MCF-7 inhibition values of 0.768 ± 0.014, 3.303 ± 0.011, and 35.714 ± 0.009 %, respectively.. Indonesia's Apis cerana has the potential to be used as a therapeutic peptide for breast cancer treatment.

Topics: Animals; Antineoplastic Agents; Bees; Breast Neoplasms; Female; Humans; Indonesia; MCF-7 Cells; Melitten

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Melitten; Signal Transduction; Tumor Microenvironment

Tumor targeting has revolutionized cancer research, especially active cellular targeting of nanoparticles, where they are specifically homed to the pathological site to deliver the therapeutics. This strategy, which involves the utilization of affinity ligands on the surface of the nanocarriers, minimizes the nonspecific uptake of nanocarriers and the subsequent harmful side effects in healthy cells. Estrone, one of the mammalian estrogens, has affinity for estrogen receptors (ERα), which are overexpressed in hormone-responsive breast cancers. Despite holding promise, the potential of estrone in active targeting of nanoparticles has barely been explored. Herein, we developed an estrone-appended polyion complex (PIC) micelle to deliver melittin, a cytotoxic peptide, to breast cancer cells. Amino functionalization of estrone was performed to conjugate estrone to the diblock polymer synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Estrone-conjugated poly(ethylene glycol) methyl ether methacrylate-

Topics: Animals; Breast Neoplasms; Drug Carriers; Estrone; Female; Humans; Melitten; Micelles; Polyethylene Glycols; Polymers

Topics: Breast Neoplasms; Cell Survival; Chromatography, Liquid; Doxorubicin; Drug Liberation; Female; Humans; Magnetite Nanoparticles; MCF-7 Cells; Melitten; Tandem Mass Spectrometry

Bee venom is a natural compound produced by the honey bee (Apis mellifera), and has been reported as having the biological and pharmacological activities, including anti-bacterial, anti-viral and anti-inflammation. In the present study, the inhibitory effects of bee venom and its major peptide components on the tumor invasion were demonstrated. It was confirmed the inhibitory effects of bee venom, melittin, and apamin on the EGF-induced invasion of breast cancer cells. Transwell invasion and wound-healing assays showed that bee venom and melittin significantly inhibits the EGF-induced invasion and migration of breast cancer cells. Also, bee venom and melittin reduced the EGF-stimulated F-actin reorganization at the leading edge, but apamin did not affect. Particularly, melittin inhibited the EGF-induced MMP-9 expression via blocking the NF-κB and PI3K/Akt/mTOR pathway. In addition, melittin significantly suppressed the EGF-induced FAK phosphorylation through inhibition of mTOR/p70S6K/4E-BP1 pathway. These results suggest that inhibitory effects of melittin on breast cancer cell motility and migration may be related to the inhibition of mTOR pathway.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Epidermal Growth Factor; Female; Focal Adhesion Kinase 1; Humans; Matrix Metalloproteinase 9; MCF-7 Cells; Melitten; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Trastuzumab (Herceptin) targets the human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-30% of breast and ovarian cancers carrying a bad prognosis. Our purpose was to target HER2-overexpressing human breast cancer cells with pegylated immunoliposomes bearing trastuzumab and containing melittin, which has recently shown anticancer properties. Using a panel of human breast cancer cells with different HER2 expression levels, these immunoliposomes decreased cancer cells viability in a dose-response manner and in correlation to their level of HER2 expression. Specific binding of the immunoliposomes to SKBr3 breast cancer cells was shown by ImageStream-based analysis. The morphological changes observed in the treated cells suggested a cytolytic process. This preclinical approach may suppose an effective strategy for the treatment of HER2-overexpressing tumors, and can support the development of an early phases I-II clinical trial. Trastuzumab resistant breast cancer cells (JIMT-1), can also be targeted using this approach.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Separation; Cell Survival; Chromatography, High Pressure Liquid; Drug Delivery Systems; Female; Flow Cytometry; Humans; Image Processing, Computer-Assisted; Liposomes; Melitten; Receptor, ErbB-2; Trastuzumab

Bee venom has been used for the treatment of inflammatory diseases such as rheumatoid arthritis and for the relief of pain in traditional oriental medicine.. The purpose of this study is to elucidate the effects of bee venom on MMP-9 expression and determine possible mechanisms by which bee venom relieves or prevents the expression of MMP-9 during invasion and metastasis of breast cancer cells. We examined the expression and activity of MMP-9 and possible signaling pathway affected in PMA-induced MCF-7 cells.. Bee venom was obtained from the National Institute of Agricultural Science and Technology of Korea. Matrigel invasion assay, wound-healing assay, zymography assay, western blot assay, electrophoretic mobility shift assay and luciferase gene assay were used for assessment.. Bee venom inhibited cell invasion and migration, and also suppressed MMP-9 activity and expression, processes related to tumor invasion and metastasis, in PMA-induced MCF-7 cells. Bee venom specifically suppressed the phosphorylation of p38/JNK and at the same time, suppressed the protein expression, DNA binding and promoter activity of NF-kappaB. The levels of phosphorylated ERK1/2 and c-Jun did not change. We also investigated MMP-9 inhibition by melittin, apamin and PLA(2), representative single component of bee venom. We confirmed that PMA-induced MMP-9 activity was significantly decreased by melittin, but not by apamin and phospholipase A(2). These data demonstrated that the expression of MMP-9 was abolished by melittin, the main component of bee venom.. Bee venom inhibits PMA-induced MMP-9 expression and activity by inhibition of NF-kappaB via p38 MAPK and JNK signaling pathways in MCF-7 cells. These results indicate that bee venom can be a potential anti-metastatic and anti-invasive agent. This useful effect may lead to future clinical research on the anti-cancer properties of bee venom.

Topics: Antineoplastic Agents; Apitherapy; Bee Venoms; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; DNA; Female; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; Melitten; Neoplasm Invasiveness; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Signal Transduction; Tetradecanoylphorbol Acetate; Transcriptional Activation

The water-soluble peptide, melittin, was modified with an anionic agent, sodium dodecyl sulfate by hydrophobic ion-pairing. Investigations showed that the formed complex was very soluble in organic solvent, especially, in dimethylsulfoxide and dehydrated alcohol. Furthermore, the physiochemical properties of the complex in the solid state or in an aqueous medium were characterized using octanol/water partition measurement, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The complex was formulated into poly(D,L-lactide-co-glycolide acid) nanoparticles by an emulsion solvent diffusion method. It was found that the nanoparticles of about 130 nm in size can be produced with a high encapsulation efficiency, and the entrapment of nanoparticles prepared with the formed complex increased from about 50% to nearly 100% compared with that for pure melittin. Moreover, the growth inhibitory effects of modified melittin and melittin-loaded nanoparticles in breast cancer MCF-7 cells were not changed comparing with free melittin as determined by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay.

Topics: Breast Neoplasms; Calorimetry, Differential Scanning; Cell Line, Tumor; Chemistry, Pharmaceutical; Dimethyl Sulfoxide; Drug Carriers; Female; Humans; Hydrophobic and Hydrophilic Interactions; Lactic Acid; Melitten; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sodium Dodecyl Sulfate; Solubility; Solvents; Spectroscopy, Fourier Transform Infrared; Surface-Active Agents

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Carriers; Female; Humans; Liposomes; Melanoma, Experimental; Melitten; Mice; Mice, Inbred C57BL; Mice, Nude; Microscopy, Electron, Transmission; Nanoparticles; Tissue Distribution

In a series of in vivo and in vitro experiments, the concept has been established that breast cancer cells that express LH/CG or LHRH receptors can be targeted and destroyed by constructs consisting of a lytic peptide moiety and a 15-amino acid segment of the beta-chain of CG or by an LHRH lytic peptide conjugate. Data obtained in vitro established the validity of this concept, showed the specificities of the Hecate-betaCG, and Phor14 and Phor21-betaCG conjugates in killing cells that express functional LH/CG receptors and proved that the LH/CG receptor capacity is directly related to the compound's specificity. In in vivo experiments, Hecate-betaCG, Phor14-betaCG, and Phor21-betaCG(ala) each caused highly significant reductions of tumor volume and tumor burden in nude mice bearing breast cancer xenografts; Hecate and Phor21 alone or conjugated with non-specific peptides were not effective. Most importantly, the lytic peptide conjugates were all highly effective in targeting and destroying disseminated breast cancer metastases in lymph nodes, bones, lungs and other organs.

Topics: Amino Acid Sequence; Animals; Breast Neoplasms; Cell Death; Chorionic Gonadotropin, beta Subunit, Human; Female; Gonadotropin-Releasing Hormone; Luciferases; Lung; Lymph Nodes; Melitten; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Metastasis; Neoplasm Transplantation; Peptide Fragments; Peptides; Spinal Cord; Tumor Burden

A 23-amino-acid synthetic lytic peptide (Hecate) was covalently linked to magnetite nanoparticles and the lytic peptide-bound nanoparticles were characterized by X-ray absorption near-edge structure spectroscopy, transmission electron microscopy, and electron diffraction. Investigation of magnetic properties with a superconducting quantum interference device (SQUID) magnetometer has shown a reduction in the saturation magnetization (Ms) of magnetite nanoparticles after binding with lytic peptide. An in vitro cell culture assay with breast cancer cell lines MDA-MB-435S revealed that the lytic peptide-bound magnetite nanoparticles were therapeutically active.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Survival; Coated Materials, Biocompatible; Drug Delivery Systems; Ferrosoferric Oxide; Humans; Iron; Lethal Dose 50; Materials Testing; Melitten; Nanotechnology; Nanotubes; Oxides; Particle Size; Surface Properties

Recent studies have shown that human and animal mammary gland carcinoma cell line express luteinizing hormone receptors (LHRs). We have examined the cytotoxic effect of Hecate-CGbeta conjugate, that is, fusion of a lytic peptide (Hecate) and a 15-amino acid fragment of the CGbeta-chain in vitro. To test the hypothesis that the Hecate-CGbeta conjugate selectively abolishes cells possessing LHR, estrogen dependent and independent human breast cancer cell lines (MCF-7; MDA-MB-231) and a mouse Leydig tumor cell line (BLT-1) were treated in vitro with Hecate-CGbeta conjugate and Hecate alone. Cytotoxic effects of the Hecate-CGbeta conjugate and the Hecate alone was measured by lactate dehydrogenase (LDH) release immediately after treatment. We observed that the Hecate-CGbeta conjugate selectively, in dose-dependent manner destroys cells possessing LHR in lower concentrations of preparate comparing to the Hecate alone and that the cytotoxic effect is strongly correlated with the number of LHR. Using Western blot analysis we characterized the LHR on membranes of MDA-MB-231, MCF-7 and BLT-1 tumor cell lines. In addition, we showed the evaluation of inhibition potential of the Hecate-CGbeta conjugate to LHR. At a concentration of 33 microM the conjugate inhibited (50%; IC50) the binding of CG to LHR. We suggest further development of this novel approach for the treatment of breast cancer by the Hecate-CGbeta for in vivo trials.

Topics: Animals; Antineoplastic Agents; Binding, Competitive; Breast Neoplasms; Carcinoma; Chorionic Gonadotropin, beta Subunit, Human; Dose-Response Relationship, Drug; Drug Delivery Systems; Humans; L-Lactate Dehydrogenase; Leydig Cell Tumor; Male; Melitten; Mice; Peptide Fragments; Receptors, LH; Recombinant Fusion Proteins; Testicular Neoplasms; Tumor Cells, Cultured

The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Chorionic Gonadotropin, beta Subunit, Human; Estradiol; Estrogen Receptor Modulators; Female; Medroxyprogesterone Acetate; Melitten; Mice; Mice, Inbred BALB C; Raloxifene Hydrochloride; Receptors, Progesterone; Tamoxifen; Tumor Cells, Cultured