Multidrug treatment can potentially overcome the resistance developed by single agents as well as reduce their side effects.26, 27 Here we have presented a novel combination treatment of melphalan in combination with the proteasome inhibitor bortezomib and the mTOR inhibitor rapamycin for colon cancer cells, as well as colon cancer stem cells, and demonstrated that this multidrug treatment-induced synergistic apoptosis mediated by AMPK activation through facilitation of Beclin-1 cleavage. This evidence concerns the gene PRKAA1 and malignant colon neoplasm.