Combining doxorubicin with a phenolic extract from flaxseed oil: Evaluation of the effect on two breast cancer cell lines

Abstract

Breast cancer is one of the most frequently diagnosed forms of cancer and different treatments are used to block its progression. However, it still represents a very common cause of death in women. Doxorubicin (Dox) is reported as an effective agent in breast cancer treatment nonetheless it induces many side‑effects. For this reason, many laboratories are engaged in understanding how it is possible to decrease the drug concentration, considering that one of the possible solutions is to use drug synergy, combining it with natural substances. Recently we showed that a phenolic extract from flaxseed (FS) oil, named PEFSO, induced on MCF‑7 cell line an increase of apoptosis with related modification of G0/G1 phase cell cycle, and the activation of signaling and pro‑oxidant pathways. In this study we present data on the combined effect of Dox and PEFSO on two different breast cancer cell lines to define the conditions to use lower doses of this chemotherapeutic agent. We report the data relating to the ability of this mixture to induce cytotoxicity and apoptosis, cell cycle modification, mitochondrial membrane depolarization and activation of extrinsic and/or intrinsic apoptotic pathway.

Mitochondrial Dysfunction Associated with Doxorubicin

“…However, rapid treatment still leads to damaged heart tissue [17]. Other toxicities of DOX have been reported to be palmar-plantar erythrodysesthesia (also known as a hand-foot syndrome) [48] and typhlitis [57]. DOX's toxic impact on tissue is associated with:…”

“…It is almost impossible to explain a single, unique apoptotic pathway induced by DOX [26]. However, literature data have suggested that DOX has been reported to trigger apoptosis in both pathways, intrinsic or mitochondrial and extrinsic [57,66].…”

“…Extrinsic pathways involve death receptors, their ligand interaction, e.g., Fas/FasL, and then caspase-8 activation [57]. DOX also uses the extrinsic pathways for instigating apoptosis by elevation of Fas protein levels, caspase-8, and BID [67] (Figure 4).…”

“…The elevation of ROS and depolarization of MMP by DOX release proapoptotic factors to the cytosol, e.g., cytochrome-c. p38, p53, Bax, and caspase-3 have also been suggested to participate in the induction of apoptosis. p53 enhances the permeability of the outer membrane to release proapoptotic factors, such as Bax [57]. DOX has been reported to increase p53 in the nucleus and mitochondria from the heart.…”

“…One study showed that DOX triggers apoptosis at the MCF-7 breast cancer cell line by elevation of caspase-3 and caspase-9 during 24 h of treatment [65]. So, p38 is one of the intrinsic pathway activators dependent on cellular stress, mitochondrial dysfunction, and caspase activation [57]. ERK1/2 probably has a role in the activation of caspase-3, Bax, p53, and cytochrome-c release.…”