The chemical properties of copper allow it to take part in many biological functions such as electron transfer, catalysis, and structural shaping. The ability to cycle between +1 and +2 oxidation state is one of the features that has been exploited by organisms throughout the evolutionary process. Since copper is potentially toxic to cells also a finely controlled mechanism for copper handling has evolved. On the other side, many copper complexes were synthesized and tested for their anticancer activity in vitro and in vivo. Their ability to kill cancer cells is mainly related to the induction of an oxidative stress, but recently it emerged their ability to inhibit the proteasome, a protein complex whose proteolitic activity is needed by several cellular process. It has generally been described that the toxic effects of copper complexes leads to cell death either by necrosis or through the activation of the apoptotic process. Evidences are rising about the ability of some copper compounds to induce alternative non-apoptotic form of programmed cell death. Since copper is indispensable for the formation of new blood vessels, angiogenesis, a different antitumor approach based on the administration of copper sequestering agents has been attempted and its effectiveness is currently under evaluation by clinical trials. The proven essentiality of copper for angiogenesis, together with the marked sensitivity shown by several cancer cell lines to the copper toxicity, open a new perspective in the anticancer strategy: exploiting the tumor need of copper to accumulate toxic amount of the metal inside its cells.

The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitin-proteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2alpha phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2alpha, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2alpha phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2alpha phosphorylation and the UPR.

Channel expansion of flexible molecular architectures endowed with porosity has been proved to be responsive to gas stimuli, such as pressurized CO₂, CH₄, Xe and hydrocarbons.