Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway

Abstract

Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.

Synthesis, molecular docking, and biological evaluation of [3,2-b]indole fused 18β-glycyrrhetinic acid derivatives against skin melanoma

“…ROS generation in cancer cells induces Endoplasmic Reticulum (ER stress) along with UPR which leads to oxidative damage that ultimately leads to apoptosis of cell thereby changing nuclear morphology. 10 A375 cells were seeded in 6 well plates (10 4 cells per well). After 24 hours, cells were subjected to treatment with different concentrations of GPD-12.…”

“…NPC-402 induced oxidative stress and apoptosis in B16F10 murine melanoma cell line. 10 In the present study, we investigated the antimelanoma activity of indole fused 18β-glycyrrhetinic acid derivatives from which GPD-12 was found to have significant effect on cell death of human A375 cell line and B16F10 murine melanoma cell line.…”

Progress in Antimelanoma Research of Natural Triterpenoids and Their Derivatives: Mechanisms of Action, Bioavailability Enhancement and Structure Modifications

“…Additionally, this compound was not toxic to HaCaT normal human keratinocytes at concentrations <50 µM. It is worth adding that the parent compound, i.e., glycyrrhetinic acid, did not affect the growth of B16F10 cells, which shows that the 3-O-prenyl substituent significantly increases the cytotoxic activity of this structure [122].…”

“…Additionally, this compound was not toxic to HaCaT normal human keratinocytes at concentrations <50 µM. It is worth adding that the parent compound, i.e., glycyrrhetinic acid, did not affect the growth of B16F10 cells, which shows that the 3-O-prenyl substituent significantly increases the cytotoxic activity of this structure [122]. Among the various amide derivatives of betulinic acid synthesized by Hoenke [116], the 4-isoquinolinyl amide of 3-O-acetyl-betulinic acid (Figure 6) showed parti activity.…”

Rhodamine B Amide Derivatives with Anticancer Activity and Fluorescence Properties for Potential Theranostic Applications

“…Cancer is known to be the second leading cause of death worldwide, and expect million of new cancer cases to rise and cancer-related deaths by 2040. [1][2] Human gastric carcinoma is one of the major causes of cancer-related deaths and mostly forms in the tissues lining the stomach and grows deeper. [3] Melanoma is also a kind of skin cancer that begins in melanocytes, cells located in the bottom layer of the skin's epidermis.…”