Carnosic acid impedes cell growth and enhances anticancer effects of carmustine and lomustine in melanoma

Abstract

Carnosic acid (CA), a major polyphenolic diterpene present in Rosmarinus officinalis, has been reported to have multiple functions, including antitumor activity. The MTT assay, BrdU incorporation, wound healing, and colony formation were used to detect melanoma B16F10 cell growth and proliferation. Flow cytometry was used for cell cycle detection. p21 and p27 expression was detected by Western blotting. B16F10 cell xenograft model was established, and treated with CA, carmustine (BCNU), or lomustine (CCNU). The present study found that CA exhibits significant growth inhibition and cell cycle arrest in melanoma B16F10 cells. We also found that CA triggers cell cycle arrest at G0/G1 phase, and enhances p21 expression. Additionally, CA can enhance BCNU- and CCNU-mediated cytotoxicity and cell cycle arrest in B16F10 cells. Finally, we found that CA inhibits tumor growth, and reduces the values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in vivo. The present study study concluded that CA may be safe and useful as a novel chemotherapeutic agent.

Characterization of Phenolic Compounds and Antiproliferative Effects of Salvia pomifera and Salvia fruticosa Extracts

“…In addition, the effects of CA alone or in combination with anti-cancer drugs on melanoma cells were described. Lin et al, 2018 [43] demonstrated the antiproliferative effect of CA in combination with carmustine or lomustine in B16F10 melanoma cells and tumors arising from B16F10 cells xenografted to the back of C57BL/6 mice. Since CA induces NQO1 expression in melanoma cells in vitro, it affects the cell proliferation and sensitizes melanoma cells to other antitumor drugs [12].…”

Carnosic acid potentiates the anticancer effect of temozolomide by inducing apoptosis and autophagy in glioma

“…CA has been widely proposed as a potential therapeutic compound in cancer treatment and prevention due to its ability to modulate cell growth and differentiation via different key molecules and signaling pathways [ 19 ]. CA impedes cell growth, induces cell cycle arrest, promotes apoptosis, and decreases mitochondrial membrane potential; CA has been shown to induce autophagy in various cancers: by enhancing p21 expression in melanoma [ 14 ] by inhibiting the AKT/mTOR pathway in hepatocellular carcinoma [ 20 ], by activating the JNK pathway in cervical cancer [ 10 ], by suppressing the Src/STAT3 pathway in renal carcinoma [ 21 ], by inhibiting the STAT3 pathway in colon cancer [ 22 ], by downregulating miR-15b in pancreatic cancer [ 23 ], and by modulating the AKT/IKK/NF-κB pathway in prostate carcinoma [ 24 ]. In glioma, Cortese et al found that CA induced cell growth arrest and apoptosis via Cyclin B1, RB and SOX2 downregulation in glioblastoma [ 11 ].…”

“…The CA and fisetin combination treatment led to enhanced inhibition of cell growth by inducing apoptosis in lung cancer [ 13 ]. CA enhanced carmustine, lomustine, and β-lapachone-induced cell growth inhibition and cell cycle arrest in melanoma [ 14 , 15 ]. However, the combination effects of CA and TMZ on glioma and the underlying molecular mechanism are still ambiguous.…”

Antiproliferative Activity of Carnosic Acid is Mediated via Inhibition of Cell Migration and Invasion, and Suppression of Phosphatidylinositol 3-Kinases (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway

“…Structurally, carnosic acid is a polyphenolic 7869 diterpene isolated from various plants including Rosmarinus officinalis. This molecule has been previously reported to exhibit various pharmacological effects including antitumor, antiviral and anti-inflammatory effects [15][16][17][18]. It has been reported that carnosic acid inhibits cell growth and induces cell cycle arrest in B16F10 melanoma cells along with enhancing p21 expression [19,20].…”