Cancer is one of the main diseases causing one-third of the worldwide death every year. The recent progresses achieved in chemotherapy have increased patients’ survival, however, drug efficacy is limited by the occurrence of serious side effects and the development of drug resistance. To overcome these problems, research interests, aim to develop alternative therapies based on the use of polyphenols, such as curcumin. Polyphenols are effective against different cancers and in combination with standard drugs, display synergism enhancing anticancer effects. Malignant mesothelioma (MM) is an aggressive cancer associated with exposure to asbestos fibers for which to date, neither surgical nor chemotherapy, based on the use of cisplatin and other platinum drugs, result in a favorable prognosis. We previously reported that daily administration of a curcumin standardized extract exerted anticancer effects in MM in vitro and in vivo . The efficacy of this formulation has been tested in several clinical trials in combination to standard drugs. Since curcumin is known to increase cisplatin sensitivity in different cancer, here we evaluated the ability of this formulation in enhancing cisplatin sensitivity in MM. The effect of combined treatment was evaluated in 2D and 3D cultures by using two MM cell lines, MSTO-211H and Ist-Mes2, that are sensitive or less responsive to the piroxicam/cisplatin combined treatment respectively. Results indicate that this treatment determines a dramatic apoptotic increase linked to a concomitant inactivation of Nrf2, a transcription factor with a key role in carcinogenesis, and of NUPR1, a transcriptional regulator involved in drug chemoresistance.