The antidiabetic compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from averrhoa carambola L., demonstrates significant antitumor potential against human breast cancer cells

Abstract

2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione found in the roots of Averrhoa carambola L., commonly known as starfruit. Researchers have shown that DMDD has significant therapeutic potential for the treatment of diabetes; however, the effects of DMDD on human cancers have never been reported. We investigated the cytotoxic effects of DMDD against human breast, lung and bone cancer cells in vitro and further examined the molecular mechanisms of DMDD-induced apoptosis in human breast cancer cells. DMDD suppressed the growth of breast carcinoma cells, but not normal mammary epithelial cells, via induction of G1 phase cell cycle arrest, oxidative stress and apoptosis. DMDD increased the level of intracellular reactive oxygen species (ROS) and DMDD-induced ROS generation was found to be associated with the mitochondrial activity. The cytotoxicity that was induced by DMDD was attenuated by co-treatment with the antioxidant N-acetyl-L-cysteine (NAC). DMDD-induced cell apoptosis involved the activation of both the intrinsic mitochondrial pathway and the extrinsic receptor pathway. In addition, DMDD inhibited the canonical NF-κB signaling pathway at all steps, including TNF-α production, phosphorylation of NF-κB p65 and IκBα, as well as TNF-α activated NF-κB p65 nuclear translocation. Collectively, our studies indicate that DMDD has significant potential as a safe and efficient therapeutic agent for the treatment of breast cancer.

2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione inhibits the growth and metastasis of breast carcinoma in mice

“…We speculate that DMDD treatment inhibits cytokine production in the tumor cells in mice, and leads to deactivation of NF-κB pathway, and consequently inhibits the expression of many anti-apoptosis and metastasis-promoting genes, such as Bcl-2 and MMPs. These in vivo observations were in agreement with our previous report on the in vitro inhibitory effect of DMDD on the NF-κB pathway in MCF-7 breast cancer cells 29 .…”

“…Utilizing human breast cancer cell lines MCF-7 and BT20, we showed that DMDD exerted its inhibitory activity through cell cycle arrest, induction of apoptosis and oxidative stress. We also showed that the in vitro inhibitory effect of DMDD on NF-κB activation occurred due to the prevention of the phosphorylation of IκBα and the nuclear translocation of NF-κB, which consequentially down-regulated the anti-apoptotic molecules and promoted apoptosis in human breast cancer cells 29 . However, the in vivo anti-tumor and anti-metastasis effects of DMDD against breast cancer have not yet been investigated.…”

“…Administration of DMDD at up to 50 mg/kg body weight for consecutive eight weeks did not show a significant difference in the renal function compared with the vehicle 28 . DMDD also exhibited significant lower toxicity to the normal human cells versus corresponding human cancer cells 29 . Because DMDD exhibited superior anti-tumor efficacy in vitro without observable toxicity, in the present study we have investigated the in vivo anti-tumor and anti-metastasis efficacy of DMDD using a 4T1 metastasis breast cancer model.…”

“…root extract, and showed that DMDD exerted anti-diabetic effects in vivo 28 . Recently, we demonstrated in vitro that DMDD had anti-proliferation efficacy against a variety of human cancer cells lines, including A549, BT20, MCF-7, MDA-MB-231 and U2OS 29 . Utilizing human breast cancer cell lines MCF-7 and BT20, we showed that DMDD exerted its inhibitory activity through cell cycle arrest, induction of apoptosis and oxidative stress.…”

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“…In vitro models have also been used to show that the compound DMDD is able to induce apoptosis in different cancer cell lines. In breast cancer cells, the compound has caused G1 phase arrest and promoted oxidative stress, and in addition it has affected the cell growth of cancer cells more than that of normal counterparts [125].…”