Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides

Vishnu Suresh Babu; Atish Kizhakeyil; Gagan Dudeja; Shyam S Chaurasia; Veluchami Amutha Barathi; Stephane Heymans; Navin Kumar Verma; Rajamani Lakshminarayanan; Arkasubhra Ghosh

doi:10.3390/pharmaceutics14112507

Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides

Vishnu Suresh Babu, Atish Kizhakeyil, Gagan Dudeja, Shyam S Chaurasia, Veluchami Amutha Barathi, Stephane Heymans, Navin Kumar Verma^*, Rajamani Lakshminarayanan^*, Arkasubhra Ghosh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities against a broad range of pathogenic bacteria by dissipating the cytoplasmic membrane potential. Specifically, we identified two CAPs, named HC3 and HC5, that effectively killed a significant number of retinoblastoma (WERI-Rb1) cells (p ≤ 0.01). These two CAPs caused the shrinkage of WERI-Rb1 tumor spheroids (p ≤ 0.01), induced intrinsic apoptosis in WERI-Rb1 cells via activation of caspase 9 and caspase 3, cleaved the PARP protein, and triggered off the phosphorylation of p53 and γH2A.X. Combining HC3 or HC5 with the standard chemotherapeutic drug topotecan showed synergistic anti-cancer activities. Overall, these results suggest that HC3 and HC5 can be exploited as potential therapeutic agents in retinoblastoma as monotherapy or as adjunctive therapy to enhance the effectiveness of currently used treatment modalities.

Original language	English
Article number	2507
Number of pages	18
Journal	Pharmaceutics
Volume	14
Issue number	11
DOIs	https://doi.org/10.3390/pharmaceutics14112507
Publication status	Published - 18 Nov 2022

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10.3390/pharmaceutics14112507Licence: CC BY

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@article{e65d6fd21cff440797e9acfae6f15e5f,

title = "Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides",

abstract = "Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities against a broad range of pathogenic bacteria by dissipating the cytoplasmic membrane potential. Specifically, we identified two CAPs, named HC3 and HC5, that effectively killed a significant number of retinoblastoma (WERI-Rb1) cells (p ≤ 0.01). These two CAPs caused the shrinkage of WERI-Rb1 tumor spheroids (p ≤ 0.01), induced intrinsic apoptosis in WERI-Rb1 cells via activation of caspase 9 and caspase 3, cleaved the PARP protein, and triggered off the phosphorylation of p53 and γH2A.X. Combining HC3 or HC5 with the standard chemotherapeutic drug topotecan showed synergistic anti-cancer activities. Overall, these results suggest that HC3 and HC5 can be exploited as potential therapeutic agents in retinoblastoma as monotherapy or as adjunctive therapy to enhance the effectiveness of currently used treatment modalities.",

author = "{Suresh Babu}, Vishnu and Atish Kizhakeyil and Gagan Dudeja and Chaurasia, {Shyam S} and Barathi, {Veluchami Amutha} and Stephane Heymans and Verma, {Navin Kumar} and Rajamani Lakshminarayanan and Arkasubhra Ghosh",

note = "Funding Information: NKV acknowledges funding support, in part, from the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 1 Grant (2020-T1-001-062), and the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (OF-LCG18May-0028) and administered by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC). RL thanks funding support from the Singapore Ministry of Health{\textquoteright}s National Medical Research Council under its Centre Grant Programme (MOH-001001-00) and Open Funding – Independent Research Grant (MOH-000963-00). The research internship of VSB in the NKV lab was supported by NKV{\textquoteright}s Start-Up Grant, LKC Medicine, Nanyang Technological University Singapore (L0412290). Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

day = "18",

doi = "10.3390/pharmaceutics14112507",

language = "English",

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journal = "Pharmaceutics",

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T1 - Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides

AU - Suresh Babu, Vishnu

AU - Kizhakeyil, Atish

AU - Dudeja, Gagan

AU - Chaurasia, Shyam S

AU - Barathi, Veluchami Amutha

AU - Heymans, Stephane

AU - Verma, Navin Kumar

AU - Lakshminarayanan, Rajamani

AU - Ghosh, Arkasubhra

N1 - Funding Information: NKV acknowledges funding support, in part, from the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 1 Grant (2020-T1-001-062), and the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (OF-LCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). RL thanks funding support from the Singapore Ministry of Health’s National Medical Research Council under its Centre Grant Programme (MOH-001001-00) and Open Funding – Independent Research Grant (MOH-000963-00). The research internship of VSB in the NKV lab was supported by NKV’s Start-Up Grant, LKC Medicine, Nanyang Technological University Singapore (L0412290). Publisher Copyright: © 2022 by the authors.

PY - 2022/11/18

Y1 - 2022/11/18

N2 - Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities against a broad range of pathogenic bacteria by dissipating the cytoplasmic membrane potential. Specifically, we identified two CAPs, named HC3 and HC5, that effectively killed a significant number of retinoblastoma (WERI-Rb1) cells (p ≤ 0.01). These two CAPs caused the shrinkage of WERI-Rb1 tumor spheroids (p ≤ 0.01), induced intrinsic apoptosis in WERI-Rb1 cells via activation of caspase 9 and caspase 3, cleaved the PARP protein, and triggered off the phosphorylation of p53 and γH2A.X. Combining HC3 or HC5 with the standard chemotherapeutic drug topotecan showed synergistic anti-cancer activities. Overall, these results suggest that HC3 and HC5 can be exploited as potential therapeutic agents in retinoblastoma as monotherapy or as adjunctive therapy to enhance the effectiveness of currently used treatment modalities.

AB - Host defense peptides represent an important component of innate immunity. In this work, we report the anticancer properties of a panel of hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues. These CAPs displayed excellent bactericidal activities against a broad range of pathogenic bacteria by dissipating the cytoplasmic membrane potential. Specifically, we identified two CAPs, named HC3 and HC5, that effectively killed a significant number of retinoblastoma (WERI-Rb1) cells (p ≤ 0.01). These two CAPs caused the shrinkage of WERI-Rb1 tumor spheroids (p ≤ 0.01), induced intrinsic apoptosis in WERI-Rb1 cells via activation of caspase 9 and caspase 3, cleaved the PARP protein, and triggered off the phosphorylation of p53 and γH2A.X. Combining HC3 or HC5 with the standard chemotherapeutic drug topotecan showed synergistic anti-cancer activities. Overall, these results suggest that HC3 and HC5 can be exploited as potential therapeutic agents in retinoblastoma as monotherapy or as adjunctive therapy to enhance the effectiveness of currently used treatment modalities.

U2 - 10.3390/pharmaceutics14112507

DO - 10.3390/pharmaceutics14112507

M3 - Article

C2 - 36432697

SN - 1999-4923

VL - 14

JO - Pharmaceutics

JF - Pharmaceutics

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ER -