The combined treatment with TOP-V122, a dual-acting NO-releasing PDE-5 inhibitor, and ionizing irradiation as a novel therapeutical strategy for colorectal carcinoma.

PURPOSE: Colorectal carcinoma is the third most common cancer globally and a major cause of cancer-related deaths. Many patients develop radiotherapy resistance, underscoring the urge for new therapies. The second messenger cGMP is crucial to maintain intestinal homeostasis, and its lack correlates with epithelial dysfunction and increased tumorigenesis. We investigated the role of TOP-V122, a dual-mode NO-releasing PDE-5 inhibitor, as an anti-tumoral drug alone and in combination with ionizing radiation.

EXPERIMENTAL

DESIGN

The therapeutic effect of TOP-V122 alone and combined with radiotherapy was assessed using patient-derived colorectal cancer organoids in vitro and in an orthotopic murine tumor model.

RESULTS

Preformed CRC organoids treated with TOP-V122 and radiotherapy showed smaller organoid size, lighter cystic structures, appeared less compact and covered a smaller area in the wells, with increased spacing between individual structures. ATP-based viability and luciferase assays confirmed enhanced anti-tumoral efficacy of the combined treatment. TOP-V122 alone did not induce DNA double-strand breaks or ROS, and while it did not prevent radiotherapy-induced double-strand breaks formation in the combined treatment, it significantly abrogated γH2AX foci formation, suggesting interference with early DNA damage signaling. KAP-1 phosphorylation was unaffected, indicating specificity for γH2AX pathways. Combined treatment further reduced the proliferative status (Ki67) and upregulated p57^Kip2 expression, whereas p21 and Wnt/β-catenin signaling (CCDN1, MYC, β-catenin) remained unchanged. In the orthotopic CRC model, oral TOP-V122 alone reduced tumor growth, and the combined treatment with radiotherapy further enhanced anti-tumoral efficacy. IVIS imaging showed a 55 % early tumor shrinkage rate with the combination, compared with 33 % and 23 % for TOP-V122 and radiotherapy alone, respectively. Terminal tumor weights confirmed these findings, with a 40 % reduction for the combined treatment versus controls. All treatments were well tolerated with stable body weight.

CONCLUSION

The PDE-5 inhibitor TOP-V122 represents a novel therapeutic option for colorectal cancer alone and in combination with radiotherapy.