Targeting STAT3 signaling with essential oils: a potential strategy for adjuvant cancer therapy

STAT3 is signaling is aberrantly active in most of the solid and hematological cancers. Constitutive activation of STAT3 plays a critical role in regulating the hallmarks of cancer, therefore STAT3 is considered as a promising target for cancer therapy. There is a growing interest in exploring natural compounds as potential anticancer agents due to the toxic effects of synthetic anticancer drugs on healthy cells and the development of chemoresistance. Essential oils (EOs) are phyto-complexes that exhibit diverse anticancer effects. In this work, from a panel of EOs, we aimed to identify EOs with potential anti-STAT3 activity and anticancer effects in DU145 human prostate cancer cells that exhibit constitutive STAT3 activation. EOs of Pinus mugo, Lavandula angustifolia, Pinus sylvestris, and Cupressus sempervirens were selected as the most potent EOs in inhibiting constitutive STAT3 phosphorylation and inducing cytotoxicity. Notably, Pinus mugo EO (PMEO) showed low cytotoxicity in non-transformed human fibroblasts, suggesting the specificity to efficiently target cancer cells. The molecular mechanism of anti-STAT3 activity was further evaluated through spectrophotometric and fluorometric analyses, and the biological effect of STAT3 inhibition was analyzed by western blotting, qRT-PCR and flow cytometry and wound healing assay. PMEO treatment induced a rapid decline in glutathione (GSH) levels and an increase in reactive oxygen species (ROS) levels, leading to oxidative stress. Pre-treatment of cells with N-acetyl-cysteine (NAC), a cell permeable ROS scavenger, reversed the inhibitory action of PMEO on STAT3 phosphorylation, suggesting that the inhibition of STAT3 activation by PMEO is mediated by ROS. The suppression of the STAT3 signaling cascade reduced the expression of pro-proliferative and anti-apoptotic genes at mRNA and protein levels, leading to the inhibition of cell migration and apoptotic cell death. Additionally, a combination treatment revealed that PMEO acts synergistically with cisplatin in inducing cytotoxicity in cancer cells. Furthermore, a nanoformulation was developed by loading PMEO into PLGA nanoparticles (PMEO-NPs) to improve the efficiency of the EO. PMEO-NPs displayed sustained release of PMEO and effective uptake by MDA-MB-231 cells in vitro and exhibited more potent anticancer activities, including enhanced cytotoxicity through ROS generation, and increased apoptotic morphology in MDAMB- 231 cells. Moreover, both PMEO and PMEO-NPs effectively suppressed breast cancer stem cell markers, indicating their potential to combat cancer stemness and aggressiveness. Additionally, the results suggest the potential use of these EOs as adjuvant or complementary therapies to enhance the effectiveness of conventional chemotherapy in the treatment of aggressive cancers

Essential oils and their nanoformulations for breast cancer therapy

Breast Cancer (BC) is the most prevalent type of cancer in the world. Current treatments include surgery, radiation, and chemotherapy but often are associated with high toxicity to normal tissues, chemoresistance, and relapse. Thus, developing novel therapies which could combat these limitations is essential for effective treatment. In this context, phytochemicals are increasingly getting popular due to their safety profile, ability to efficiently target tumors, and circumvent limitations of existing treatments. Essential Oils (EOs) are mixtures of various phytochemicals which have shown potential anticancer activity in preclinical BC models. However, their clinical translation is limited by factors such as high volatility, low stability, and poor solubility. Nanotechnology has facilitated their encapsulation in a variety of nanostructures and proven to overcome these limitations. In this review, we have efficiently summarized the current knowledge on the anticancer effect of EOs and constituents in both in in vitro and in in vivo BC models. Further, we also provide a descriptive account on the potential of nanotechnology in enhancing the anti-BC activity of EOs and their constituents. The papers discussed in this review were selected using the keywords "antiproliferative Essential Oils in breast cancer," "anticancer activity of Essential Oil in breast cancer," and "cytotoxicity of Essential Oils in breast cancer" performed in PubMed and ScienceDirect databases

Pinus mugo Essential Oil Impairs STAT3 Activation through Oxidative Stress and Induces Apoptosis in Prostate Cancer Cells

Essential oils (EOs) and their components have been reported to possess anticancer properties and to increase the sensitivity of cancer cells to chemotherapy. The aim of this work was to select EOs able to downregulate STAT3 signaling using Western blot and RT-PCR analyses. The molecular mechanism of anti-STAT3 activity was evaluated through spectrophotometric and fluorometric analyses, and the biological effect of STAT3 inhibition was analyzed by flow cytometry and wound healing assay. Herein, Pinus mugo EO (PMEO) is identified as an inhibitor of constitutive STAT3 phosphorylation in human prostate cancer cells, DU145. The down-modulation of the STAT3 signaling cascade decreased the expression of anti-proliferative as well as anti-apoptotic genes and proteins, leading to the inhibition of cell migration and apoptotic cell death. PMEO treatment induced a rapid drop in glutathione (GSH) levels and an increase in reactive oxygen species (ROS) concentration, resulting in mild oxidative stress. Pretreatment of cells with N-acetyl-cysteine (NAC), a cell-permeable ROS scavenger, reverted the inhibitory action of PMEO on STAT3 phosphorylation. Moreover, combination therapy revealed that PMEO treatment displayed synergism with cisplatin in inducing the cytotoxic effect. Overall, our data highlight the importance of STAT3 signaling in PMEO cytotoxic activity, as well as the possibility of developing adjuvant therapy or sensitizing cancer cells to conventional chemotherapy