Compared with BTZ alone, representing the first PI available for MM patients, they showed that 2-methoxyestradiol (2ME), which is a natural estrogen metabolite, induced a higher rate of MM cell death, due to increases in the mitochondrial ROS and Ca2+ levels in the cells, the activation of c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase 4/7 (MKK4/7) [17]. This evidence concerns the gene MAP2K4 and Miyoshi myopathy.