melitten and Prostatic-Neoplasms

Prostate cancer is one of the most common cancers in men. Despite the development of a variety of therapeutic agents to treat either metastatic hormone-sensitive prostate cancer, advanced prostate cancer, or nonmetastatic/metastatic castration-resistant prostate cancer, the progression or spread of the disease often cannot be avoided. Additionally, the development of resistance of prostate cancer cells to available therapeutic agents is a well-known problem. Despite extensive and cost-intensive research over decades, curative therapy for metastatic prostate cancer is still not available. Therefore, additional therapeutic agents are still needed. The animal kingdom offers a valuable source of natural substances used for the treatment of a variety of diseases. Bee venom of the honeybee is a mixture of many components. It contains proteins acting as enzymes such as phospholipase A2, smaller proteins and peptides such as melittin and apamin, phospholipids, and physiologically active amines such as histamine, dopamine, and noradrenaline. Melittin has been shown to induce apoptosis in different cancer cell lines, including prostate cancer cell lines. It also influences cell proliferation, angiogenesis, and necrosis as well as motility, migration, metastasis, and invasion of tumour cells. Hence, it represents an interesting anticancer agent. In this review article, studies about the effect of bee venom components on prostate cancer cells are discussed. An electronic literature research was performed utilising PubMed in February 2021. All scientific publications, which examine this interesting subject, are discussed. Furthermore, the different types of application of these promising substances are outlined. The studies clearly indicate that bee venom or melittin exhibited anticancer effects in various prostate cancer cell lines and in xenografts. In most of the studies, a combination of bee venom or the modified melittin with another molecule was utilised in order to avoid side effects and, additionally, to target selectively the prostate cancer cells or the surrounding tissue. The studies showed that systemic side effects and unwanted damage to healthy tissue and organs could be minimised when the anticancer drug was not activated until binding to the cancer cells or the surrounding tissue. Different targets were used, such as the matrix metalloproteinase 2, hormone receptors expressed by prostate cancer cells, the extracellular domain of PSMA, and the fibroblas

Topics: Animals; Antineoplastic Agents; Apamin; Apoptosis; Bee Venoms; Bees; Humans; Male; Melitten; Phospholipases A2; Prostatic Neoplasms

In a series of in vivo and in vitro experiments, it was shown that membrane disrupting lytic peptides (Hecate, Phor14, or Phor21) conjugated to a 15 amino acid segment of the beta chain of CG or to LHRH were able to target and destroy hormone dependent and independent human prostate cancer xenografts in nude mice. In vitro sensitivity of the cells to the drugs was directly related to LH/CG receptor expression, and pretreatment in vitro or in vivo with estrogens or FSH to enhance LH/CG receptor expression capacity and increased sensitivity to the drugs. Administration of unconjugated Hecate and LHRH was ineffective. Most importantly, all of the lytic peptide-betaCG conjugates tested were highly effective in destroying prostate cancer metastatic cells in lymph nodes, bones and lungs.

Topics: Animals; Carcinoma; Cell Survival; Chorionic Gonadotropin, beta Subunit, Human; Gonadotropin-Releasing Hormone; Humans; Male; Melitten; Necrosis; Neoplasm Metastasis; Prostatic Neoplasms

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

Prostate cancer is the second leading cause of death due to cancer in men. Owing to shortcomings in the current treatments, other therapies are being considered. Toxic gene delivery is one of the most effective methods for cancer therapy. Cationic polymers are able to form stable nanoparticles via interaction with nucleic acids electrostatically. Branched polyethylenimine that contains amine groups has notable buffering capacity and the ability to escape from endosome through the proton sponge effect. However, the cytotoxicity of this polymer is high, and modification is one of the applicable strategies to overcome this problem. In this study, PEI was targeted with chlorotoxin (CTX) via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) cross-linker. CTX can bind specifically to matrix metalloproteinase-2 that is overexpressed in certain cancers. Melittin as the major component of bee venom has been reported to have anti-cancer activity. This was thus selected to deliver to PC3 cell line. Flow cytometry analysis revealed that transfection efficiency of targeted nanoparticles is significantly higher compared to non-targeted nanoparticles. Targeted nanoparticles carrying the melittin gene also decreased cell viability of PC3 cells significantly while no toxic effects were observed on NIH3T3 cell line. Therefore, CTX-targeted nanoparticles carrying the melittin gene could serve as an appropriate gene delivery system for prostate and other MMP-2 positive cancer cells.

Topics: Animals; Cell Line, Tumor; Cell Survival; Gene Transfer Techniques; Genetic Therapy; Humans; Male; Matrix Metalloproteinase 2; Melitten; Mice; Nanoparticles; NIH 3T3 Cells; Polyethyleneimine; Polymers; Prostatic Neoplasms; Scorpion Venoms; Transfection

Some antimicrobial peptides have emerged as potential anticancer agents. In contrast to chemotherapeutics, they act primarily by physical disruption of the cancer cell membrane. Selective targeting of these cationic peptides still remains elusive. We focus on the interaction of α-helical peptides NK-2, cathelicidin LL32, and melittin with PC-3 prostate cancer cells, and we provide strong evidence that, amongst the anionic glycans covering the cell surface, sulphated carbohydrates rather than sialic acids are the preferred interaction sites of the peptides. To test the significance of cell surface carbohydrates, a glycan microarray screen with fluorescently labelled peptides has been performed. Amongst 465 mammalian glycan structures on the chip, more than 20 different sulphated glycans were detected as the preferred binding partners of the peptide NK-2. The amount of peptide bound to sialic acid containing oligosaccharides was close to background level. These findings were consistent with microcalorimetric experiments revealing high and low binding enthalpies of peptides to sulphated carbohydrates and to sialic acid, respectively. Enzymatic desialylation of PC-3 cells did not affect peptide-mediated changes in cell metabolism, cell membrane permeabilisation, killing rate, and kinetics. Finally, the cytotoxicity of all peptides could be drastically impaired through the competitive inhibition by chondroitin sulphate, but not by sialic acid and sialylated fetuin.

Topics: Amino Acid Sequence; Antimicrobial Cationic Peptides; Antineoplastic Agents; Carbohydrate Sequence; Cathelicidins; Cell Line, Tumor; Cell Membrane; Cell Membrane Permeability; Cell Survival; Humans; Male; Melitten; Molecular Sequence Data; Peptides; Polysaccharides; Prostatic Neoplasms; Sialic Acids; Sulfates

Bee venom has been used as a traditional medicine to treat arthritis, rheumatism, back pain, cancerous tumors, and skin diseases. However, the effects of bee venom on the prostate cancer and their action mechanisms have not been reported yet.. To determine the effect of bee venom and its major component, melittin on the prostate cancer cells, apoptosis is analyzed by tunnel assay and apoptotic gene expression. For xenograft studies, bee venom was administrated intraperitoneally twice per week for 4 weeks, and the tumor growth was measured and the tumor were analyzed by immunohistochemistry. To investigate whether bee venom and melittin can inactivate nuclear factor kappa B (NF-κB), we assessed NF-κB activity in vitro and in vivo.. Bee venom (1-10 µg/ml) and melittin (0.5-2.5 µg/ml) inhibited cancer cell growth through induction of apoptotic cell death in LNCaP, DU145, and PC-3 human prostate cancer cells. These effects were mediated by the suppression of constitutively activated NF-κB. Bee venom and melittin decreased anti-apoptotic proteins but induced pro-apoptotic proteins. However, pan caspase inhibitor abolished bee venom and melittin-induced apoptotic cell death and NF-κB inactivation. Bee venom (3-6 mg/kg) administration to nude mice implanted with PC-3 cells resulted in inhibition of tumor growth and activity of NF-κB accompanied with apoptotic cell death. Therefore, these results indicated that bee venom and melittin could inhibit prostate cancer in in vitro and in vivo, and these effects may be related to NF-κB/caspase signal mediated induction of apoptotic cell death.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bee Venoms; Caspases; Cell Line, Tumor; Humans; Male; Melitten; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Prostatic Neoplasms; Xenograft Model Antitumor Assays

A Hecate-CGbeta conjugate (lytic peptide and beta-chorionic gonadotropin) selectively destroyed cells possessing LH receptors. This study described functional characteristics of the conjugate and the molecular mechanism of the cell death pathway in prostate cancer cells. Based on in vitro studies, we conclude that the conjugate kills cells possessing luteinizing hormone receptors (LHR) faster than Hecate alone. Competitive studies have shown that blocking of LHR by preincubation with chorionic gonadotropin (100 ng/ml) reduced toxicity of the conjugate in low concentrations. Further studies have also shown that the conjugate in treated cells both did not induce internucleosomal DNA fragmentation and did not induce morphological changes in cells characterized as having apoptotic features. These results proved that cells died by necrosis rather than apoptosis after the conjugate treatment.

Topics: Animals; Cell Line, Tumor; Cell Membrane; Chorionic Gonadotropin; Chorionic Gonadotropin, beta Subunit, Human; Gene Expression; Humans; L-Lactate Dehydrogenase; Male; Melitten; Mice; Necrosis; Prostatic Neoplasms; Receptors, LH; RNA, Messenger

Monoclonal antibodies (MAbs) can target therapy to tumours while minimising normal tissue exposure. Efficacy of immunoconjugates containing peptide 101, designed around the first 22 amino acids of bee venom, melittin, to maintain the amphipathic helix, to enhance water solubility, and to increase hemolytic activity, was assessed in nude mice bearing subcutaneous human prostate cancer xenografts.. Mouse MAbs, J591 and BLCA-38, which recognise human prostate cancer cells, were cross-linked to peptide 101 using SPDP. Tumour-bearing mice were used to compare biodistributions of radiolabeled immunoconjugates and MAb, or received multiple sequential injections of immunoconjugates. Therapeutic efficacy was assessed by delay in tumour growth and increased mouse survival.. Radiolabeled immunoconjugates and antibodies showed similar xenograft tropism. Systemic or intratumoural injection of immunoconjugates inhibited tumour growth in mice relative to carrier alone, unconjugated antibody and nonspecific antibody-peptide conjugates and improved survival for treated mice.. Immunoconjugates deliver beneficial effects; further peptide modifications may increase cytotoxicity.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Cell Division; Cross-Linking Reagents; Cytotoxicity, Immunologic; Flow Cytometry; Humans; Immunoconjugates; In Vitro Techniques; Male; Melitten; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Peptide Fragments; Prostatic Neoplasms; Succinimides; Survival Rate; Tumor Cells, Cultured

Monoclonal antibodies (MAbs) are used for targeting agents to tumours while minimizing normal tissue exposure.. A new anti-prostate cancer MAb, BLCA-38, was radioiodinated (I125) and assessed for its ability to target subcutaneous human prostate cancer (DU-145) xenografts after systemic intraperitoneal administration. For comparison, the profile of J591 MAb (now in clinical trial) against LNCaP-LN3 tumours was examined. Biodistribution profiles were obtained at various times, by assessing injected dose/gram (%ID/g) and xenograft to blood (X/B) ratios. Microautoradiography of xenografts was performed. After conjugation with a melittin peptide toxin, the profiles of BLCA-38 and J591 were compared with that of an irrelevant antibody, DS-1.. Xenograft localization by 125I-labeled BLCA-38 and J591 MAbs to their relevant antigen-positive tumors was comparable, and there was no unusual localization in nontumour tissues. F(ab')2 and Fab fragments gave improved X/B ratios, but the %ID/g xenograft was decreased and they accumulated in kidneys, bladder and stomach. In contrast, the conjugates of irrelevant antibody showed no tumour targeting. Microautoradiography showed more tumour accumulation of MAbs than F(ab')2s or Fabs.. BLCA-38 can target prostate cancer in vivo almost as effectively as J591. Given that J591 is used clinically, BLCA-38, which targets a different antigen, has potential for radioimmunoscintigraphy and for therapeutic targeting of prostate cancer.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Neoplasm; Cytotoxicity, Immunologic; Gastric Mucosa; Humans; Immunoglobulin Fab Fragments; Injections, Intraperitoneal; Iodine Radioisotopes; Kidney; Male; Melitten; Mice; Mice, Inbred BALB C; Mice, Nude; Peptide Fragments; Prostatic Neoplasms; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured; Urinary Bladder

A conjugate of a lytic peptide, hecate, and a 15-amino acid segment of the beta-chain of chorionic gonadotropin (CG) destroyed human prostate xenografts in nude mice by targeting LH receptors. Since these xenografts also express LHRH receptors, we prepared a LHRH-hecate conjugate and tested its ability to destroy PC-3 cells in vitro and in vivo.. LHRH-hecate was added to cultures of PC-3, BRF 41 T, DU145, and LNCaP cells in the presence and absence of steroids. PC-3 xenografts were established in nude male mice, which were treated with LHRH-hecate.. Injections of LHRH-hecate resulted in tumor growth arrest and marked reduction of tumor burden (62.2 mg/g body weight in saline controls vs. 10.5 mg/g body weight in treated mice; P < 0.0001); unconjugated LHRH and hecate had no effect on tumor burden and tumor viability (48.5 mg/g body weight in LHRH treated animals vs. 63.2 mg/g body weight in hecate treated mice). Marked tumor necrosis occurred in conjugate treated mice. Removal of steroids from the culture media decreased the sensitivity of LNCaP and PC-3 cells to the LHRH-hecate; adding estrogen restored the sensitivity.. LHRH-hecate may be effective in treating hormone dependent and independent prostate cancers.

Topics: Animals; Body Weight; Cell Death; Culture Media; Gonadotropin-Releasing Hormone; Humans; Male; Melitten; Mice; Mice, Nude; Necrosis; Neoplasms, Experimental; Peptides; Prostatic Neoplasms; Receptors, LHRH; Steroids; Transplantation, Heterologous; Tumor Cells, Cultured

We have prepared a conjugate of a lytic peptide (hecate) and a 15-amino acid segment of the beta-chain of LH to test the concept that this conjugate will target cancer cells expressing LH receptors.. Hecate-betaLH was added in vitro to cultures of Chinese hamster ovary (CHO) cells with and without LH receptors and to prostate cancer cells in the presence or absence of steroids, follicle-stimulating hormone (FSH), epidermal growth factor (EGF), or betaLH. PC-3 xenografts were established in male athymic nude mice and treated once a week for 3 weeks with hecate-betaLH via the lateral tail vein.. The conjugate showed concentration-dependent toxicity for the following prostate cancer cell lines: BRF 41 T>DU145>PC-3>LNCaP, according to their LH receptor capacities. Steroid removal reduced sensitivity to the drug in a reversible manner. Hecate-betaLH reduced the tumor burden in the nude mice from 60 to 12.5 mg/g body weight.. We conclude that the hecate-betaLH conjugate selectively kills androgen-dependent and-independent prostate cancer cells both in vivo and in vitro; its toxicity depends on the number of LH receptor sites present.

Topics: Amino Acid Sequence; Animals; Charcoal; CHO Cells; Cricetinae; Drug Carriers; Epidermal Growth Factor; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Male; Melitten; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Neoplasms, Hormone-Dependent; Peptide Fragments; Prostatic Neoplasms; Receptors, LH; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays