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Letters to the Editor
(Online Supplementary Figure S3). After 3 days (Online Supplementary Figure S3A, B) and 6 days (Online Supplementary Figure S3C, D) of treatment, we evaluated drug effects. Both maraviroc and trabectedin decreased heterospheroid cell viability in a dose-dependent manner and their combination further increased cytotoxicity. These effects were more evident after 6 days of treat- ment in HDLM-2 and in particular in L-1236 cells (Online Supplementary Figure S3).
To demonstrate that the direct contact with cHL-MSC can protect against the effects exerted by maraviroc, tra- bectedin and their combination, HRS cells and cHL-MSC were cultured under non-adherent conditions and drugs were added before (at T=0) and after (at T=24h) their spontaneous aggregation in heterospheroids (see Figure 3A). After 6 days cell viability of heterospheroids formed by L-1236/cHL-MSC (Figure 3B) and by HDLM-2/cHL- MSC (Figure 3C) was evaluated. Both maraviroc and tra- bectedin alone reduced cell viability of heterospheroids (Figure 3B, C) and their combination was significantly more efficacious than single treatments. Cytotoxicity was more evident when drugs were added before cell aggregation (heterospheroid formation, T=0) (black his- tograms), suggesting a protective role of HL-MSC and cooperation between the two cell types, including the increased secretion and expression of pro-survival fac- tors.13 Representative phase contrast photographs demonstrating the increased cytotoxic activity of the combination trabectedin-maraviroc in heterospheroids are shown in Figure 3D.
Taken together our results suggest that maraviroc can enhance trabectedin activity by reducing the tumor-pro- moting effects of the direct contact of HRS cells with cHL-MSC13 and by inhibiting autocrine and paracrine effects induced by CCL5 secreted by HRS cells6 and tumor-educated cHL-MSC.5
In conclusion, maraviroc synergized with trabectedin, enhanced trabectedin-induced DNA double-strand breaks and decreased the protective effects of cHL-MSC in heterospheroids.
Therefore, this study offers an additional preclinical rationale for the use of maraviroc as a new therapeutic option to affect tumor microenvironmental interactions, to enhance the cytotoxic activity of DNA-damaging agents and, by decreasing their doses, to reduce adverse side effects.5 These findings provide insights for future research to investigate the possibility of potentiating the antitumoral activity of DNA-damaging agents, including gamma radiation, currently used for the treatment of cHL.15
Naike Casagrande, Cinzia Borghese and Donatella Aldinucci
Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
Correspondence:
DONATELLA ALDINUCCI- daldinucci@cro.it
doi:10.3324/haematol.2021.279389 Received: June 29, 2021.
Accepted: August 27, 2021.
Pre-published: September 9, 2021. Disclosures: no conflicts of interest to disclose.
Contributions: NC and CB generated and interpreted the data; DA and NC drafted the manuscript; DA supervised the study. All authors reviewed, revised, and approved the final manuscript.
Acknowledgments: the authors thank Dr. Alfonso Colombatti for his help with reviewing the manuscript.
Funding: this work was supported in part by grant IG 15844 from the Italian Association for Cancer Research (to DA) and by the Italian Ministry of Health (Ricerca Corrente).
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