BODIPYs in PDT: A Journey through the Most Interesting Molecules Produced in the Last 10 Years

Over the past 30 years, photodynamic therapy (PDT) has shown great development. In the clinical setting the few approved molecules belong almost exclusively to the porphyrin family; but in the scientific field, in recent years many researchers have been interested in other families of photosensitizers, among which BODIPY has shown particular interest. BODIPY is the acronym for 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene, and is a family of molecules well-known for their properties in the field of imaging. In order for these molecules to be used in PDT, a structural modification is necessary which involves the introduction of heavy atoms, such as bromine and iodine, in the beta positions of the pyrrole ring; this change favors the intersystem crossing, and increases the O-1(2) yield. This mini review focused on a series of structural changes made to BODIPYs to further increase O-1(2) production and bioavailability by improving cell targeting or photoactivity efficiency

Preliminary toxicity Evaluation of a porphyrin photosensitizer in an alternative preclinical Model

In photodynamic therapy (PDT), a photosensitizer (PS) excited with a specific wavelength, and in the presence of oxygen, gives rise to photochemical reactions that lead to cell damage. Over the past few years, larval stages of the G. mellonella moth have proven to be an excellent alternative animal model for in vivo toxicity testing of novel compounds and virulence testing. In this article, we report a series of preliminary studies on G. mellonella larvae to evaluate the photoinduced stress response by a porphyrin (PS) (TPPOH). The tests performed evaluated PS toxicity on larvae and cytotoxicity on hemocytes, both in dark conditions and following PDT. Cellular uptake was also evaluated by fluorescence and flow cytometry. The results obtained demonstrate how the administration of PS and subsequent irradiation of larvae affects not only larvae survival rate, but also immune system cells. It was also possible to verify PS’s uptake and uptake kinetics in hemocytes, observing a maximum peak at 8 h. Given the results obtained in these preliminary tests, G. mellonella appears to be a promising model for preclinical PS tests

Biological activity of enantiomeric complexes [PtCl2L2](L2 is aromatic bisphosphanes and aromatic diamines)

Enantiomeric complexes of formula [PtCl(2)L(2)] [L(2) is (R)-(+)-BINAP and (S)-(-)-BINAP, where BINAP is 2,2'-bis(diphenylphosphane)-1,1'-binaphthyl, and (R)-(+)-DABN and (S)-(-)-DABN, where DABN is 1,1'-binaphthyl-2,2'-diamine], were tested for their cytotoxic activity against three cancer cell lines and for their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar experiments were carried out on prototypal complexes cisplatin and cis-[PtCl(2)(PPh(3))(2)] for comparison. Platinum complexes containing phosphanes proved less cytotoxic to cancer cell lines and less likely to interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-(-) isomer was more active than the R-(+) counterpart. More specifically, whereas all the platinum complexes were able to platinate the G-quadruplex structure from the human telomeric repeat, the extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky) phosphanes interacted only with the adenines of the loops, whereas those containing the less sterically demanding amines interacted with adenines and some guanines of the G-quartet

Free and poly-methyl-methacrylate-bounded BODIPYs: photodynamic and antimigratory effects in 2D and 3D cancer models

Several limitations, including dark toxicity, reduced tumor tissue selectivity, low photostability and poor biocompatibility hamper the clinical use of Photodynamic therapy (PDT) in cancer treatment. To overcome these limitations, new PSs have been synthetized, and often combined with drug delivery systems, to improve selectivity and reduce toxicity. In this context, BODIPYs (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) have recently emerged as promising and easy-to-handle scaffolds for the preparation of effective PDT antitumor agents. In this study, the anticancer photodynamic effect of newly prepared negatively charged polymethyl methacrylate (nPMMA)-bounded BODIPYs (3@nPMMA and 6@nPMMA) was evaluated on a panel of 2D- and 3D-cultured cancer cell lines and compared with free BODIPYs. In particular, the effect on cell viability was evaluated, along with their ability to accumulate into the cells, induce apoptotic and/or necrotic cell death, and inhibit cellular migration. Our results indicated that 3@nPMMA and 6@nPMMA reduce cancer cell viability in 3D models of HC116 and MCF7 cells more effectively than the corresponding free compounds. Importantly, we demonstrated that MDA-MB231 and SKOV3 cell migration ability was significantly impaired by the PDT treatment mediated by 3@nPMMA and 6@nPMMA nanoparticles, likely indicating the capability of this approach to reduce metastatic tumor potential

Antiproliferative effects of interleukin-1α and nitric oxide release in a human ovarian carcinoma cell line

Interleukin-1 (IL-1) exerts direct antiproliferative effects on a number of human tumor cell lines, but the mechanisms involved are still poorly understood. Nitric oxide (NO) has been shown to mediate some of the actions of IL-1. Therefore, we investigated the role played by NO in the cytostatic effects of IL-1 alpha on NIH:OVCAR-3 cells, a cell line which has been shown to possess IL-1 receptors and to respond to the cytokine with growth arrest; the involvement of NO release in the synergistic interaction between IL-1 alpha and adriamycin (ADR) observed in this cell line was also studied. 72 h exposure to concentrations of IL-1 alpha similar to its IC50 value, were found to enhance NO release. This was significantly reduced by co-incubation with 1 mM L-NAME, which however did not significantly affect the IC50 values, either for IL-1 alpha or for the combination IL-1 alpha:ADR (1:20,000). We conclude that induction of NO synthesis in IL-1 alpha-treated cells is probably a side effect originating from transcription factor activation by the cytokine, and that neither the antiproliferative effects of IL-1 alpha nor its potentiation of ADR cytotoxicity depend on NO release

Targeting Mitochondrial ROS Production to Reverse the Epithelial-Mesenchymal Transition in Breast Cancer Cells

Experimental evidence implicates reactive oxygen species (ROS) generation in the hypoxic stabilization of hypoxia-inducible factor (HIF)-1 alpha and in the subsequent expression of promoters of tumor invasiveness and metastatic spread. However, the role played by mitochondrial ROS in hypoxia-induced Epithelial-Mesenchymal Transition (EMT) activation is still unclear. This study was aimed at testing the hypothesis that the inhibition of hypoxia-induced mitochondrial ROS production, mainly at the mitochondrial Complex III UQCRB site, could result in the reversion of EMT, in addition to decreased HIF-1 alpha stabilization. The role of hypoxia-induced ROS increase in HIF-1 alpha stabilization and the ability of antioxidants, some of which directly targeting mitochondrial Complex III, to block ROS production and HIF-1 alpha stabilization and prevent changes in EMT markers were assessed by evaluating ROS, HIF-1 alpha and EMT markers on breast cancer cells, following 48 h treatment with the antioxidants. The specific role of UQCRB in hypoxia-induced EMT was also evaluated by silencing its expression through RNA interference and by assessing the effects of its downregulation on ROS production, HIF-1 alpha levels, and EMT markers. Our results confirm the pivotal role of UQCRB in hypoxic signaling inducing EMT. Thus, UQCRB might be a new therapeutic target for the development of drugs able to reverse EMT by blocking mitochondrial ROS production

Platinum(IV) combo prodrugs containing cyclohexane-1R,2R-diamine, valproic acid, and perillic acid as a multiaction chemotherapeutic platform for colon cancer

The complex [PtCl2(cyclohexane-1R,2R-diamine)] has been combined in a Pt(iv) molecule with two different bioactive molecules (i.e., the histone deacetylase inhibitor 2-propylpentanoic acid or valproic acid, VPA, and the potential antimetastatic molecule 4-isopropenylcyclohexene-1-carboxylic acid or perillic acid, PA) in order to obtain a set of multiaction or multitarget antiproliferative agents. In addition to traditional thermal synthetic procedures, microwave-assisted heating was used to speed up their preparation. All Pt(iv) complexes showed antiproliferative activity on four human colon cancer cell lines (namely HCT116, HCT8, RKO and HT29) in the nanomolar range, considerably better than those of [PtCl2(cyclohexane-1R,2R-diamine)], VPA, PA, and the reference drug oxaliplatin. The synthesized complexes showed pro-apoptotic and pro-necrotic effects and the ability to induce cell cycle alterations. Moreover, the downregulation of histone deacetylase activity, leading to an increase in histone H3 and H4 levels, and the antimigratory activity, indicated by the reduction of the levels of matrix metalloproteinases MMP2 and MMP9, demonstrated the multiaction nature of the complexes, which showed biological properties similar to or better than those of VPA and PA, but at lower concentrations, probably due to the lipophilicity of the combo molecule that increases the intracellular concentration of the single components (i.e., [PtCl2(cyclohexane-1R,2R-diamine)], VPA and PA)

Luteolin impairs hypoxia adaptation and progression in human breast and colon cancer cells.

Hypoxia-inducible factors (HIFs) are the force which drive hypoxic cancer cells to a more aggressive and resistant phenotype in a number of solid tumors, including colorectal and breast cancer. Results from recent studies suggest a role for HIF-1 in immune evasion and cancer stem cell phenotype promotion, establishing HIF-1 as a potential therapeutic target. Thus identifying new compounds that might inhibit HIF1 activity, or at least exert antiproliferative effects that are unaffected by HIF1-dependent adaptations, is an attractive goal for the management of hypoxic tumors. Here we show that the flavonoid luteolin exerts a significant cytotoxic effect on the colon cancer cell line HCT116 and the breast adenocarcinoma cell line MDA-MB231, by inducing both apoptotic and necrotic cell death, and that this effect is not impaired by HIF-1 activation. In these cells, luteolin also stimulates autophagy; however this seems to be part of a protective response, rather than contribute to the cytotoxic effect. Interestingly, luteolin induces a decrease in HIF-1 transcriptional activity. This is accompanied by a decrease in the levels of protein markers of stemness and invasion, and by a reduction of migratory capacity of the cells. Taken together, our results suggest that luteolin could be developed into a useful therapeutic agent aimed at hypoxic tumors

Rhein to impart antimetastatic features to Pt(IV) complexes and to target brain

The combination of an anticancer Pt drug and another coadjutant molecule with different biological targets is a promising therapeutic strategy. Octahedral Pt(IV) complexes allow to combine cisplatin-like moieties and a second anticancer agent in a single molecule to obtain potential bifunctional antiproliferative prodrugs. Indeed, in the hypoxic and reducing tumor environment Pt(IV) complexes are activated by a two-electron reduction to form an active Pt(II) metabolite with concomitant loss of the second agent, when linked to the metal in axial position. The natural anthranoid rhein or cassic acid has several pharmacological effects and exerts anticancer effects by modulating cellular proliferation, apoptosis, migration, and invasion. Moreover, it can inhibit in vivo glioma tumor progression. For this reason, cisplatin-based Pt(IV) derivatives were synthesized by differently linking rhein to the metal. The complexes proved to be similar to or more potent than cisplatin and rhein, and temozolomide (reference drug) on glioblastoma cells. The Pt(IV) complexes caused a significant decrease in the motility of cells, which can be related to inhibition of matrix metalloproteinases