Scheme 2.

Proposed molecular mechanism leading to carcinogenic drift by S100B aberrant release in tissue milieu and relative pharmacological regulation exerted by PENVE. (A) S100B accumulates at RAGE site and inhibits wtp53 functions leading to RAGE‐dependent lipid peroxidation, with consequent phosphor p‐38/NF‐kappaB mediated release of pro‐angiogenic (VEGF), pro‐inflammatory (IL‐6, iNOS) and factors leading to cell migration and invasion (AQP4). Inhibition of wtp53 and Bax is accompanied by a massive increase of pro‐proliferative PCNA, with consequent enhancement of cell proliferation and resistance to apoptotic surveillance. (B) In the presence of pentamidine, carried by the PENVE system, the S100B‐wtp53 complex is disengaged and wtp53 functions are restored. Consequently, downstream signals due to S100B‐RAGE interaction are down‐regulated, leading to a reduction of VEGF, IL‐6, iNOS, and AQP4 signals. Restored wtp53, is accompanied to up‐regulation of Bax and pro‐apoptotic surveillance of scarcely PCNA expressing cell proliferating