8 research outputs found
Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial
Synthesis, characterization, and biological activity of platinum II, III, and IV pivaloamidine complexes
Synthesis, characterization, and biological activity of platinum II, III, and IV pivaloamidine complexes
Imino ligands have proven to be able to activate the trans geometry of platinum(II) complexes towards antitumor activity. These ligands, like aromatic N-donor heterocycles, have a planar shape but, different from the latter, have still an H atom on the coordinating nitrogen which can be involved in H-bond formation. Three classes of imino ligands have been extensively investigated: iminoethers (HN=C(R)OR'), ketimines (HN=CRR'), and amidines (HN=C(R)NR'R\u2033). The promising efficacy of the platinum compounds with amidines (activity comparable to that of cisplatin for cis complexes and much greater than that of transplatin for trans complexes) prompted us to extend the investigation to amidine complexes with a bulkier organic residue (R = t-Bu). The tert-butyl group can confer greater affinity for lipophilic environments, thus potentiating the cellular uptake of the compound. In the present study we describe the synthesis and characterization of pivaloamidine complexes of platinum(II), (cis and trans-[PtCl2(NH3){Z-HN=C(t-Bu)NH2}] and cis and trans-[PtCl2{Z-HN=C(t-Bu)NH2}2]), platinum(III) ([Pt2Cl4{HN=C(t-Bu)NH}2(NH3)2]), and platinum(IV) (trans-[PtCl4(NH3){Z-HN=C(t-Bu)NH2}] and trans-[PtCl4{Z-HN=C(t-Bu)NH2}2]). The cytotoxicity of all new Pt complexes was tested toward a panel of cultured cancer cell lines, including cisplatin and multidrug resistant variants. In addition, cellular uptake and DNA binding, perturbations of cell cycle progression, induction of apoptosis, and p53 activation were investigated for the most promising compound trans-[PtCl2(NH3){Z-HN=C(t-Bu)NH2}]. Remarkably, the latter complex was able to overcome both acquired and intrinsic cisplatin resistance
Novel Antitumor Cisplatin and Transplatin Derivatives Containing 1‑Methyl-7-Azaindole: Synthesis, Characterization, and Cellular Responses
The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active ta
“Exosomes-Mediate Crosstalk in Multiple Myeloma progression and drug Resistance”
Purpose: Exosomes (EXOs) mediate local and systemic cell-tocell
communication and regulate cell behavior by transferring
mRNA, miRNAs and proteins to recipient cells. Recently,
we demonstrated that bone marrow (BM) cancer associated
fibroblasts (CAFs) promote tumor progression and drug
resistance (DR) in multiple myeloma (MM) (1-3). In this study, we
analysed the effect of MM-derived EXOs on CAFs in MGUS to
MM transition and, in turn, the effect of CAFs-derived EXOs on
endothelial (ECs) and MM cells.
Methods: EXOs isolation was performed from conditioned
medium (CM) of CAFs purified from BM aspirates of 8 active MM
patients and from CM of cultured RPMI8226 and U266 MM cells.
Electron microscopy (TEM), dual immunofluorescence-confocal
laser-scanning microscopy, western blot (WB), flow cytometry
(FC) and qRT-PCR studies were performed to evaluate the CAFsand
MM-derived EXOs phenotypes, their miRs content and their
mutual effect.
Results: TEM analysis of CAFs- and MM-derived EXOs showed
a vesicles population with heterogeneous aspect, 50-100 nm
sized. WB analysis defined the expression of commonly used
EXOs surface markers as CD63, Hsp70 for CAFs and CD63,
Hsp70, Alix for MM cells. Confocal microscopy showed the
ability both CAFs and MM cells to uptake respectively MM- and
CAFs-derived EXOs labelled with fluorescent dyes. Functional
studies showed that MM-derived EXOs induce a specific miRNA
profile as overexpression of miR-27b-3p, -125b-5p, -214-3p
and activated phenotype, as expression of FAP+ and SMA+
antigens, in MGUS and MM CAFs. In turn, MM CAFs released
EXOs containing miR-27b-3p, -125b-5p, -214-3p are swallowed
by MM cells and ECs. Functional studies also showed that CAFsderived
EXOs are able to stimulate angiogenic ability in ECs and
to induce bortezomib-resistance in MM cells.
Discussions and Conclusions: Overall results suggest an
important exosomal crosstalk among tumor cells, CAFs and ECs
which lead to BM microenvironmental modifications, favouring
MM progression and DR.
References
1. Frassanito MA et al. Leukemia 2014; 28: 904-16.
2. Frassanito MA et al. Leukemia 2016; 30: 640-8.
3. Di Marzo L et al. Oncotarget 2016; 7: 60698-711