Synergistic Anticancer Effects of Essential Oil from Pistacia atlantica subsp mutica Peel and Doxorubicin on Gastrointestinal Cancer Cells

Nahid Askari (PhD)^1*, Morvarid Bayat (MSc)¹, Amirhesan Yahyapour (MSc)¹, Setayesh Sadat Hosseini (MSc)¹

¹ Department of Biotechnology, Institute of Sciences and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran

Received: 14.03.2024  Accepted: 29.05.2024

Abstract

Background: Developing less toxic therapies for gastrointestinal cancers is crucial, as doxorubicin chemotherapy causes severe side effects and drug resistance. This research investigated combining doxorubicin with wild pistachio peel essential oil (WPPEO). Plant compounds like WPPEO possess antioxidant properties that may reduce doxorubicin-induced oxidative stress. Their anti-inflammatory effects could also sensitize cancer cells to treatment. The study focuses on this combination's potential to enhance therapeutic efficacy while mitigating the significant limitations of standard doxorubicin use.

Materials and Methods: MTT assays assessed the cytotoxicity of WPPEO and doxorubicin, individually and combined, in gastric (MKN), liver (HepG2), colorectal (SW480) cancer cells, and normal fibroblasts (SKM). Synergy was evaluated via isobologram analysis. RT-PCR quantified BAX and BCL-2 gene expression to measure apoptosis induction.

Results: Doxorubicin and WPPEO synergistically reduced HepG2 viability to 32.4% (CI<1). WPPEO selectively targeted cancer cells, exhibiting 2-2.5 times lower toxicity to normal cells (IC₅0=251 µg/mL) compared to cancer cells (IC₅₀: 100-125 µg/mL). Isobologram analysis confirmed this synergy, which sensitized cancer cells to doxorubicin-induced cell death via the intrinsic apoptosis pathway, increasing the pro-apoptotic BAX/BCL-2 ratio by 30-fold.

Conclusions: Doxorubicin and WPPEO worked together to significantly reduce the viability of HepG2 cancer cells to 32.4% (with a confidence interval less than 1). WPPEO selectively targeted cancer cells, showing 2 to 2.5 times lower toxicity to normal cells (IC50 = 251 µg/mL) compared to cancer cells (IC50: 100-125 µg/mL). An isobologram analysis confirmed this synergistic effect, which made cancer cells more sensitive to cell death induced by doxorubicin through the intrinsic apoptosis pathway. This was evidenced by a 30-fold increase in the pro-apoptotic BAX/BCL-2 ratio.

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