The endoplasmic reticulum (ER) is critical in aiding cells in ensuring that proteins are folded and processed correctly, particularly during stressful situations. ER oxidoreductin-1 alpha (ERO1α) is an enzyme that is responsible for the formation of disulfide bonds during protein folding, along with protein disulfide isomerase (PDI). This redox pathway is often highly upregulated in cancer cells, allowing tumors to survive harsh conditions such as hypoxia and nutrient deprivation. This review discusses the role of the ERO1α–PDI system in cancer development through the regulation of oxidative stress, redox homeostasis, and tumor plasticity. It further shows the therapeutic potential of interrupting the ERO1α–PDI axis, which could lead to protein misfolding; enhanced generation of reactive oxygen species (ROS); and, eventually, cancer cell death.

Phenformin, a representative of the biguanides class was previously used for treatment of type 2 diabetes and discontinued due to a risk of causing lactic acidosis, has shown promising anticancer activity in numerous studies. Since many types of cancer arise and proliferate due to dysregulation in apoptotic or autophagic pathways, this study aimed to assess the underlying anticancer effects of phenformin in terms of these two processes. We initially set out to examine the antiproliferative effects of phenformin on multiple cancer cell lines including breast, pancreatic, cervical cancers, hepatocellular carcinoma and malignant melanoma. Subsequently, the expression of apoptosis and autophagy related proteins was measured in the cervical cancer cell lines found to be the most susceptible to antiproliferative effects of phenformin. Additionally, the ability of phenformin to potentiate the antitumor effect of resveratrol and vistusertib was assessed. Phenformin increased the expression of pro-apoptotic factor, Bax, and lowered the level of anti-apoptotic protein, Bcl-2. Hence, it was proposed that phenformin promotes antiproliferative activity by inducing apoptosis. Our findings demonstrate that phenformin decreases the proliferation of various cancer cell lines in a dose-dependent manner and may have an ability to increase the autophagic flux in cervical cancer cells. Our findings demonstrate that phenformin decreases the proliferation of various cancer cell lines in a dose-dependent manner potentially by inducing apoptosis.