Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling

Pereira, Gustavo José Vasco; Tavares, Maurício Temotheo; Azevedo, Ricardo A.; Martins, Barbara Behr; Cunha, Micael Rodrigues; Bhardwaj, Rajesh; Cury, Yara; Zambelli, Vanessa O.; Barbosa, Euzébio Guimarães; Hediger, Matthias A.; Parise-Filho, Roberto

doi:10.1016/j.bmc.2019.05.020

Cited by 17 publications

(16 citation statements)

References 63 publications

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“…The mentioned Ca 2+ influx elevates [Ca 2+ ] i (Table S2): ref. [34,35,[37][38][39]43,46,[48][49][50]54,55,65,[68][69][70][71][72][73][74][75][76][77][78][79]. The co-application of TRPV1 antagonists, including capsazepine, ruthenium red (RR) and idioresiniferatoxin (I-RTX), attenuates agonist-induced Ca 2+ influx; furthermore, capsazepine alone reduces [Ca 2+ ] i (Table S9): ref.…”

Section: The Apoptotic Pathway and Upstream Cytosolic Effectsmentioning

confidence: 99%

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Zhai

Líšková

Kubatka

et al. 2020

IJMS

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Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening of transient receptor potential vanilloid 1 (TRPV1) ligand-gated ion channels facilitates transmembrane Ca2+ and Na+ entry, which modifies the delicate balance between apoptotic and proliferative signaling pathways. Proliferation is upregulated through two mechanisms: (1) ATP binding to the G-protein-coupled receptor P2Y2, commencing a kinase signaling cascade that activates the serine-threonine kinase Akt, and (2) the transactivation of the epidermal growth factor receptor (EGFR), leading to a series of protein signals that activate the extracellular signal-regulated kinases (ERK) 1/2. The TRPV1-apoptosis pathway involves Ca2+ influx and efflux between the cytosol, mitochondria, and endoplasmic reticulum (ER), the release of apoptosis-inducing factor (AIF) and cytochrome c from the mitochondria, caspase activation, and DNA fragmentation and condensation. While proliferative mechanisms are typically upregulated in cancerous tissues, shifting the balance to favor apoptosis could support anti-cancer therapies. TRPV1, through [Ca2+]i signaling, influences cancer cell fate; therefore, the modulation of the TRPV1-enforced proliferation–apoptosis balance is a promising avenue in developing anti-cancer therapies and overcoming cancer drug resistance. As such, this review characterizes and evaluates the role of TRPV1 in cell death and survival, in the interest of identifying mechanistic targets for drug discovery.

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Section: The Apoptotic Pathway and Upstream Cytosolic Effectsmentioning

confidence: 99%

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Zhai

Líšková

Kubatka

et al. 2020

IJMS

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“…This has been reported to act through induction of both apoptosis and autophagy [10], downregulation of Bcl-2 with enhanced apoptosis [15], downregulation of IL-8 with reduced cell proliferation [13], and suppression of B16F10 cell migration via PI3K/Akt/Rac1 pathway [16]. Unsurprisingly, capsaicin has been used as a prototype for the design and synthesis of analogs aimed at inducing selective apoptosis in melanoma cells [41]. Capsaicin has also been shown to have a synergistic effect when combined with other drugs: It has been shown to further delay tumor growth in a dose-dependent fashion in mice with lung (LLC), bladder (MBT-2), and melanoma (B16F10) cancers [42].…”

Section: Discussionmentioning

confidence: 99%

Capsaicin Exerts Therapeutic Effects by targeting tNOX-SIRT1 Axis and Augmenting ROS-Dependent Cytotoxic Autophagy in Melanoma Cancer Cells

Islam

Hsieh

Liu

et al. 2020

Preprint

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Background: Although considered a rare form of skin cancer, malignant melanoma has steadily increased internationally and is a main cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effects of capsaicin on the growth of melanoma cells.Methods: The cellular thermal shift assay (CETSA) and isothermal dose response fingerprint (ITDRFCETSA) were utilized to validate the binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analysis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice.Results: Our data show that capsaicin directly targets cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin is accompanied by the attenuation of SIRT1, a NAD+-dependent deacetylase that enhances ULK1 acetylation to induce ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Conclusions: Together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting cytotoxic ROS-dependent autophagy in melanoma cells.

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“…Furthermore, the V1-cal peptide (1 μg/paw in 20 μL, GenScript) or TAT 47–57 (1 μg/paw in 20 μL, Genscript) was administrated intraplantarly 15 minutes before capsaicin or Brp-LPA injection. Immediately after injection, nociceptive behavior (paw-licking and flinching) was quantified for 5 minutes immediately after injection ( 19 , 61 ). Paw thickness was also measured 20 minutes after capsaicin injection using a digital caliper placed near the injection site.…”

Section: Methodsmentioning

confidence: 99%

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents

Zambelli

Sinharoy

et al. 2023

Journal of Clinical Investigation

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Pain signals are relayed to the brain via a nociceptive system, and in rare situations, this nociceptive system contains genetic variants that can limit pain response. Here we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and further if we can target this region by a cell-permeable peptide as a pain therapeutic.Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1 K710N knock-in mouse using CRISPR/Cas9, we discovered the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1 K710N rodents also had less acute behavioral response to chemical noxious stimuli and less hypersensitivity to nerve injury, while leaving the response to noxious heat intact. Furthermore, blocking this K710 region in wild-type rodents by a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and rescued pain hypersensitivity induced by nerve injury back to baseline. These findings identify K710 TRPV1 as a discrete site crucial for the control of nociception and provides insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

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Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling

Cited by 17 publications

References 63 publications

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells

Capsaicin Exerts Therapeutic Effects by targeting tNOX-SIRT1 Axis and Augmenting ROS-Dependent Cytotoxic Autophagy in Melanoma Cancer Cells

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents

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