Synthesis of breast cancer targeting conjugate of temporin-SHa analog and its effect on pro- and anti-apoptotic protein expression in MCF-7 cells

Shaheen, Farzana; Nadeem-ul-Haque, Muhammad; Ahmed, Aqeel; Simjee, Shabana Usman; Ganesan, A.; Jabeen, Almas; Shah, Zafar Ali; Choudhary, Muhammad Iqbal

doi:10.1016/j.peptides.2018.07.002

Cited by 17 publications

(18 citation statements)

References 39 publications

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“…To the best of our knowledge, this is the first report on NBD peptide to have necrotic activity in T24 bladder cancer cell line. Our observations in this study was in accordance with other studies that state different cell lines do respond differently to a treatment based on their cancer phenotype (McConnell et al, 2015); the factors that cause a peptide to act differently in a tumor microenvironment (Pan et al, 2014); the amino acid difference from the originally reported NBD peptide (May et al, 2000;Dai et al, 2004;May et al, 2002) and the different cell penetrating peptide tags that allow them to act unlike their original counterparts (Shaheen et al, 2018).…”

supporting

confidence: 91%

Selective Susceptibility of Human Bladder Transitional Cell Carcinoma T24 Cells towards NBD Peptide

Durairajan¹,

Walter²,

Kalaiselvi³

et al. 2020

American Journal of Biochemistry and Biotechnology

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Bladder cancer is a recurrent disease that often develops chemoresistance and is on the rise in developing countries. After diagnosis surgery followed by immunotherapy and/or chemo-radiation therapy are the available treatments. These treatments do not provide protection against disease progression or recurrence thus highlighting the need to identify and develop drugs that are capable of inhibiting bladder cancer. T24 cell line (human bladder transitional cell carcinoma) was treated with NEMO Binding Domain (NBD) peptide and tested for its cytotoxicity, cell cycle inhibition, apoptosis and migration, in vitro. The cytotoxicity of NBD peptide was tested on non-cancerous cells (NIH-3T3-L1, CHO, Vero) and the peptide localization in T24 cells was confirmed using confocal microscopy. The effects of NBD peptide and the standard drugs (cisplatin, gemcitabine) were compared with untreated control. Peptide based chemotherapy for human bladder cells was tested that include combinations of NBD and standard drugs. Statistical significance was assessed between the different treatment groups. The viability of T24 cells after NBD peptide treatment was reduced to 50% at a dose of 18.5 µM after 48 h. The NBD peptide elicited selective cytotoxicity dose-dependently in T24 cells while being non-toxic on normal (non-cancer) cell lines. Sub G0-G1 accumulation of T24 cells was seen where they underwent necrosis and lost the ability to migrate when treated with 100 µM NBD. T24 cell death increased to ~78% when treated with a combination of NBD with cisplatin and gemcitabine (standard drugs) as opposed to ~50% when treated with NBD peptide alone. NBD peptide exhibits specific anti-cancer activity on T24 cells in vitro and found to be non-cytotoxic to select normal cell lines. Combining NBD with standard drugs demonstrated excellent inhibition of malignant growth than the individual anti-neoplastic agents.

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supporting

confidence: 91%

Selective Susceptibility of Human Bladder Transitional Cell Carcinoma T24 Cells towards NBD Peptide

Durairajan¹,

Walter²,

Kalaiselvi³

et al. 2020

American Journal of Biochemistry and Biotechnology

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“…Temporins are a class of HDPs with antibacterial and antitumor activities, reported from a wide range of frogs of the Ranidae family [26]. A few of the family members like Temporin-1CEa, TemporinA, and Temporin-SHa are shown to have antitumor activities against certain cancer types [27,28,29]. The selective cytotoxicity of TemporinA towards lung cancer cells is attributed to the speci c phospholipid composition of lung cancer cells [27].…”

Section: Discussionmentioning

confidence: 99%

SSTP1, A Host Defense Peptide, Exploits the Immunomodulatory Il6 Pathway to Induce Apoptosis in Cancer Cells

Shyla

Mohan

et al. 2021

Preprint

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Background: The anticancer activities of host defense peptides (HDPs) are mainly attributed to their cell penetrating activity. Accordingly, several approaches based on machine learning, calculating the membrane pore formation ability, have been proposed for the anti-cancer peptide identification. Since the membranolytic activity can lead to nonspecific effects, like hemolysis, the therapeutic application of such molecules is limited. In this context, we considered the immunomodulatory activity of HDPs, which is regulated by specific membrane targets and immunomodulatory pathways in immune cells. As many immunomodulators are aberrantly expressed in cancer cells, the possibility of the activation of an immunomodulatory pathway was investigated for a novel anticancer HDP, SSTP1.Methods: The fourteen mature peptides identified by shotgun cloning from the frog-skin secretions were screened for cytotoxicity in oral cancer cells. The mechanism of action of the selected peptide, SSTP1 was investigated in comparison to its inactive mutant, SSTP2. An RNA-Seq coupled with pathway enrichment analysis was performed to identify the upstream signaling leading to the mitochondrial pathway of apoptosis. Since the activation of the IL6/IL6R pathway was suggested, we performed in silico docking studies to find the binding of SSTP1 to the IL6/IL6Rα/gp130 complex. The dynamic simulation predicted the conformational changes in the active site residues. The confocal co-localization studies, pull-down assay, FRET analysis, western blot and reporter assays were performed to elucidate the role of the IL6/IL6R pathway in SSTP1-induced apoptosis. Specific small molecule inhibitors and neutralizing antibodies were used to ascertain the role of the IL6/IL6Rα/gp130 complex in the activation of JNK/AP1 pathway-dependent cell death.Results: SSTP1, a novel temporin, modulates the IL6 pathway and induces apoptosis when it binds to IL6Rα on the active IL6/IL6Rα/gp130 complex, rearranging the active site residues. In contrast to the IL6 blockers inhibiting JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. In IL6Rα-overexpressing cancer cells, apoptosis is preferred over the membranolytic activity, upon SSTP1 treatment.Conclusions: Here, we provide the evidence of an HDP-induced signaling through immunomodulators, leading to apoptosis in cancer cells. Our study also implies the importance of identifying the targets of HDPs for their clinical application

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“…They were produced by substitution of one or more of the stereochemically more flexible achiral Gly found on the positions 4, 7, and 10 by D-Ala or L-Ala. These analogs were previously shown to possess anticancer properties, [G10a]SHa (NST1) containing D-Ala in place of Gly at position 10 was the more active on cancer cells [22,23]. The antibacterial activity of temporin-SHa and its analogs against H. pylori was first evaluated using MIC determination on the reference ATCC strain.…”

Section: Discussionmentioning

confidence: 99%

“…The pure peptide products were obtained by purification on RP-HPLC using the isocratic solvent system. The peptides were charaterized by matrix-assisted laser desorption/ ionization-time of flight (MALDI-TOF) mass spectrometry, HR-MALDITOF-MS, MALDI/MS/MS and NMR studies [22].…”

Section: Methodsmentioning

confidence: 99%

“…Recently, new analogs of temporin-SHa (SHa) were synthetized with substitution of Gly residues at positions 4, 7, and/or 10 with D-Ala or L-Ala (Table 1). These analogues showed interesting anticancer activity, particularly temporin[G10a]-SHa (NST1) that was found very potent against difference cancer cell lines [22]. One interesting thing previously shown by Shah et al is the dramatic increase in the activity of temporin-LK1 when single Gly was substituted by D-Ala [23].…”

Section: Introductionmentioning

confidence: 99%

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Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori

et al. 2019

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Helicobacterpylori is one of the most prevalent pathogens colonizing 50% of the world’s population and causing gastritis and gastric cancer. Even with triple and quadruple antibiotic therapies, H. pylori shows increased prevalence of resistance to conventional antibiotics and treatment failure. Due to their pore-forming activity, antimicrobial peptides (AMP) are considered as a good alternative to conventional antibiotics, particularly in the case of resistant bacteria. In this study, temporin-SHa (a frog AMP) and its analogs obtained by Gly to Ala substitutions were tested against H. pylori. Results showed differences in the antibacterial activity and toxicity of the peptides in relation to the number and position of D-Ala substitution. Temporin-SHa and its analog NST1 were identified as the best molecules, both peptides being active on clinical resistant strains, killing 90–100% of bacteria in less than 1 h and showing low to no toxicity against human gastric cells and tissue. Importantly, the presence of gastric mucins did not prevent the antibacterial effect of temporin-SHa and NST1, NST1 being in addition resistant to pepsin. Taken together, our results demonstrated that temporin-SHa and its analog NST1 could be considered as potential candidates to treat H. pylori, particularly in the case of resistant strains.

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Synthesis of breast cancer targeting conjugate of temporin-SHa analog and its effect on pro- and anti-apoptotic protein expression in MCF-7 cells

Cited by 17 publications

References 39 publications

Selective Susceptibility of Human Bladder Transitional Cell Carcinoma T24 Cells towards NBD Peptide

Selective Susceptibility of Human Bladder Transitional Cell Carcinoma T24 Cells towards NBD Peptide

SSTP1, A Host Defense Peptide, Exploits the Immunomodulatory Il6 Pathway to Induce Apoptosis in Cancer Cells

Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori

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