Abstract:BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as th… Show more
“…A.M. Yu, UC Davis. The tamoxifen (TAM) resistant lines were maintained in MCF7 base media supplemented with 1 μM or 5 μM TAM [44]. The mitoxantrone resistant line (MX-100) was maintained as previously described [45].…”
Amiloride and its derivatives have long attracted attention as potential anticancer therapeutic agents. Several original studies characterized amilorides as inhibitors of sodium-proton antiporter tumor growth and urokinase plasminogen activator-mediated metastasis. However, more recent observations indicate that amiloride derivatives are specifically cytotoxic toward tumor cells relative to normal cells and have the capacity to target tumor cell populations resistant to currently-employed therapies. A major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with EC50 values in the high micromolar to low millimolar range. Here we report structure-activity relationship observations that underscore the importance of the guanidinium group and the presence of lipophilic substituents at the C(5) position of the amiloride pharmacophore in promoting cytotoxicity. Moreover, we demonstrate that our most potent derivative called LLC1 is cytotoxic toward mouse mammary tumor organoids and drug-resistant populations of various breast cancer cell lines, and induces lysosomal membrane permeabilization as a prelude to lysosome-dependent cell death. Our observations offer a roadmap for the future development of amiloride-based cationic amphiphilic drugs that engage the lysosome to specifically kill breast tumor cells.
“…A.M. Yu, UC Davis. The tamoxifen (TAM) resistant lines were maintained in MCF7 base media supplemented with 1 μM or 5 μM TAM [44]. The mitoxantrone resistant line (MX-100) was maintained as previously described [45].…”
Amiloride and its derivatives have long attracted attention as potential anticancer therapeutic agents. Several original studies characterized amilorides as inhibitors of sodium-proton antiporter tumor growth and urokinase plasminogen activator-mediated metastasis. However, more recent observations indicate that amiloride derivatives are specifically cytotoxic toward tumor cells relative to normal cells and have the capacity to target tumor cell populations resistant to currently-employed therapies. A major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with EC50 values in the high micromolar to low millimolar range. Here we report structure-activity relationship observations that underscore the importance of the guanidinium group and the presence of lipophilic substituents at the C(5) position of the amiloride pharmacophore in promoting cytotoxicity. Moreover, we demonstrate that our most potent derivative called LLC1 is cytotoxic toward mouse mammary tumor organoids and drug-resistant populations of various breast cancer cell lines, and induces lysosomal membrane permeabilization as a prelude to lysosome-dependent cell death. Our observations offer a roadmap for the future development of amiloride-based cationic amphiphilic drugs that engage the lysosome to specifically kill breast tumor cells.
Background
Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1–15, 1996; An et al. in Ann Neurol 40:611–6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174–5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al. in Aids 33:1843–1852, 2019; Mintzopoulos et al. in Magn Reson Med 81:2896–2904, 2019), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid–delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown.
Methods
We used the simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (Molina et al. in AIDS Res Hum Retroviruses 27:585–592, 2011) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells.
Results
Significant changes in BG-EV-associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV-infected rhesus macaques (SIV EVs) contained 11 significantly downregulated miRNAs. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV–THC EVs). Most of these miRNAs are predicted to regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and altered the expression of CD40, TNFα, MMP-2, and MMP-2 gene products in primary mouse astrocytes in an EV and CX3CR1 dependent manners.
Conclusions
Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV- and THC-induced changes within the CNS.
“…Thus, targeting BST-2 may be a versatile option for the treatment of breast cancer patients (Mahauad-Fernandez and Okeoma 2018 ). As the backbone of their cytotoxic anti-cancer agent, Yuan Lyu et al ( 2020 ) used the BST-2 anti-adhesion peptide B18, a second-generation anti-adhesion peptide against BST-2. They designed five peptidomimetics based on B18.…”
Section: New Opportunity Of Peptidomimetic For Cancer Drug Resistancementioning
confidence: 99%
“…5 ). Studies on B18L have shown that this peptidomimetic decreases Src and Erk1/2, enhances Bcl2 pro-apoptotic proteins, and triggers caspase bed processing in breast cancer (Lyu et al 2020 ). Fig.…”
Section: New Opportunity Of Peptidomimetic For Cancer Drug Resistancementioning
The low efficiency of treatment strategies is one of the main obstacles to developing cancer inhibitors. Up to now, various classes of therapeutics have been developed to inhibit cancer progression. Peptides due to their small size and easy production compared to proteins are highly regarded in designing cancer vaccines and oncogenic pathway inhibitors. Although peptides seem to be a suitable therapeutic option, their short lifespan, instability, and low binding affinity for their target have not been widely applicable against malignant tumors. Given the peptides’ disadvantages, a new class of agents called peptidomimetic has been introduced. With advances in physical chemistry and biochemistry, as well as increased knowledge about biomolecule structures, it is now possible to chemically modify peptides to develop efficient peptidomimetics. In recent years, numerous studies have been performed to the evaluation of the effectiveness of peptidomimetics in inhibiting metastasis, angiogenesis, and cancerous cell growth. Here, we offer a comprehensive review of designed peptidomimetics to diagnose and treat cancer.
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