cis-Diammineplatinum(II) dichloride, best known as cisplatin (CDDP), is a platinum-containing agent currently employed for the treatment of a large array of solid tumors, encompassing head and neck, lung, colorectal, bladder, prostate, ovarian and germ cell cancers.1
For a long time, CDDP has been considered as a pure DNA-damaging agent, promoting the formation of intra- and inter-strand DNA adducts that eventually result in the activation of (often apoptotic) cell death or senescence.2,3
Nowadays, following the demonstration that CDDP also exerts cytotoxic effects on enucleated cells,4,5
and that only 1% of intracellular CDDP binds nuclear DNA,6
it has become clear that the signaling pathways underlying the antineoplastic effects of CDDP are complex and integrate cytoplasmic (post-translational, rapid)7
and nuclear (transcriptional, delayed) mechanisms.8
Testicular germ cell cancer patients receiving CDDP-based chemotherapy undergo complete and durable regressions in a sizeable fraction (> 80%) of cases, and these individuals can de facto be considered as cured.9
In other clinical settings, including colorectal, lung and prostate cancer, the percentage of patients that are intrinsically resistant to CDDP-based chemotherapy is significantly higher. Moreover, a consistent fraction of originally sensitive tumors eventually develop chemoresistance, which rapidly translates into relapse and therapeutic failure.10,11
Besides relatively mild side effects (including nausea, vomiting and appetite loss), CDDP, which is generally administered as a short-term infusion in physiological saline, can be associated with grade I–II nephrotoxicity (in more than 30% of patients), neurotoxicity and ototoxicity (both in 10–30% of patients).1
This said, the most critical limitation to the clinical use of CDDP as an antineoplastic agents is provided by the high incidence of innate and acquired chemoresistance.
During the last two decades, the molecular mechanisms whereby cancer cells elude the antineoplastic activity of CDDP have been the subject of intense investigation. The detailed description of these pathways largely exceeds the scope of this introduction and can be found elsewhere.10,12
Still, it is worth noting that cancer cells can avoid CDDP cytotoxicity at least at four different levels: (1) by avoiding its intracellular accumulation and/or availability (pre-target resistance); (2) by repairing CDDP-induced DNA lesions more proficiently (on-target resistance); (3) by interrupting the signaling cascades that normally bridge DNA damage to the execution of cell death or the activation of cell senescence (post-target resistance) and (4) via alterations in signaling cascades that are not directly elicited by CDDP, yet compensate for CDDP-driven lethal signals.10
Moreover, it should be noted that, in the vast majority of cases, CDDP resistance appears to be multifactorial, i.e., to involve the simultaneous activation of several non-overlapping mechanisms, de facto complicating the development of clinically meaningful strategies of chemosensitization.10
During the last few years, our attention has been centered on the molecular mechanisms that are activated by CDDP in non-small cell lung carcinoma (NSCLC), a frequent and aggressive form of lung cancer that is responsible for more than 1 million deaths worldwide annually.13,14
Here, we report the results of a multipronged experimental approach revealing that CDDP activates signaling pathways that are mainly “private,” i.e., that manifest limited overlap with the molecular cascades elicited by prototypic inducers of mitochondrial apoptosis, such as C2-ceramide (C2-CER) and cadmium dichloride (CdCl2
). Moreover, we show that functional modifiers of the cytotoxic response of NSCLC cancer cells to CDDP are generally not subjected to transcriptional regulation during CDDP-induced cell death, and that, when they are, this reflects the activation of an adaptive response to CDDP.