141 - Increased proliferation/aggressiveness and metastatic potential of therapy targeted surviving breast adenocarcinoma cells as well as bystander non-targeted cancer cells; role of therapy-induced iNOS/NO, and beneficial effects of iNOS inhibitors

Abstract

We have recently uniquely shown that human breast cancer cells (adenocarcinoma MDA-MB 231), exploit endogenous nitric oxide (NO) to resist elimination by photodynamic therapy (PDT), cisplatin (CDDP) chemotherapy or combination of both. Inducible nitric oxide synthase (iNOS) was rapidly and persistently upregulated after the treatment challenge, and the resulting NO signaled not only for greater resistance, but also greater growth, migration, and invasion aggressiveness of not only cancer cells surviving the challenge, but also bystander cells which escaped initial therapy. Ionizing radiation of specifically targeted cells in a given population is known to elicit pro-death or pro-survival responses in non-targeted bystander cells, but far less is known about such effects in the case of non-ionizing therapies. We will report on our most recent studies testing hypothesis that photodynamically or pharmacologically stressed breast adenocarcinoma cells can elicit NO-mediated pro-growth/migration aggressive responses not only in surviving target cells but also in non-stressed bystander cells. Switching to a more aggressive phenotype during clinical therapeutic treatment (either PDT or chemo/PDT) would be an alarming prospect because it might lead to greater cancer metastatic spread. We will also report on our attempts to overcome/minimize such effects by using classical inhibitors of iNOS activity (s.a. 1400W) and recently introduced bromodomain and extra-terminal domain (BET) transcriptional inhibitors (s.a. JQ1). (Supported by NCN grant 2017/27/B/NZ5/02620).