An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil’s Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer

Abstract

Antimetabolites, especially 5-fluorouracil, are commonly used clinically to treat breast, colon, and other cancers. However, their side effects and inefficiency in monotherapy have prompted further searches for new combinations. Thus, the anticancer effect of 5-fluorouracil (5-FU) and the sulforaphane analogue, 4-isoselenocyanato-1-butyl 4′-fluorobenzyl sulfoxide (ISC), were tested in in vitro and in vivo models of triple-negative breast cancer (TNBC) as a new option for this treatment-resistant and aggressive type of breast cancer. A synergic interaction between 5-FU and ISC was observed in the TNBC in vitro model MDA-MB-231 cell line, which led to enhanced antiproliferative effects. The results of in vitro studies were confirmed by in vivo tests, which demonstrated stronger tumor growth inhibition and additive interactions between 5-FU and ISC in the murine TNBC model. Moreover, the results of the body mass and blood analysis showed the safety of the tested combination. The mechanistic study revealed that the combined treatment triggered apoptosis and necrosis, as well as inhibited cell migration.

Dietary isothiocyanates and anticancer agents: exploring synergism for improved cancer management

“…The combination index (CI) values varied across cell lines, suggesting that the nature of interaction depends on the specific characteristics of each cancer cell line. In vivo studies further corroborated these in vitro results, with a combination of 5-FU and an SFN analog, 4-isoselenocyanato-1-butyl 4-fluorobenzyl sulfoxide (ISC), showing reduced tumor volume and metastasis in a mammary gland carcinoma animal model, indicating potentiated anticancer activity ( 86 ). Moreover, SFN’s combination with FOLFOX (5-FU, oxaliplatin, and folinic acid) in highly metastatic human colon carcinoma cells led to a marked decrease in cell viability, enhanced apoptosis, and inhibited spheroid formation while modulating aldehyde dehydrogenase 1 (ALDH1) activity.…”

“…The observed synergistic effects, as evidenced by CI values less than 1, indicate the potential for improved therapeutic outcomes. However, it is important to note that the combinational effects of SFN and anticancer drugs are not always synergistic (67, 69,85,91). This highlights the complexity of drug interactions and the need for careful consideration of the specific cellular context when evaluating combination therapies.…”

“…Apoptosis, a programmed cell death mechanism crucial for removing damaged or unwanted cells, is a common target for ITCs and anticancer drugs. Studies have shown that ITCs, such as SFN and PEITC, can sensitize cancer cells to apoptosis induced by various chemotherapeutic agents (17,69,72,85,98). This sensitization often involves the upregulation of death receptors (DR), such as DR5, and the activation of both intrinsic and extrinsic apoptotic pathways (32,66,81).…”

“…ITCs have been documented to induce cell cycle arrest at various checkpoints, thereby halting the proliferation of cancer cells (98)(99)(100). When ITCs are combined with chemotherapeutic agents that also disrupt the cell cycle, such as 5-FU, the result can be a more pronounced inhibition of cancer cell growth (69,85). This effect is likely due to the complementary mechanisms of action, whereby ITCs modulate key cell cycle regulators, such as p21, and enhance the cytostatic effects of the drugs (67, 69).…”

First Generation of Antioxidant Precursors for Bioisosteric Se-NSAIDs: Design, Synthesis, and In Vitro and In Vivo Anticancer Evaluation

“…The efficacy of selenocompounds as anticancer agents is correlated with their metabolic route, dose, and the chemical form of Se [ 5 , 18 ]. Hence, the main Se entities that have been widely explored to date are selenides [ 19 , 20 , 21 , 22 ], selenocyanates [ 22 , 23 , 24 , 25 , 26 ], isoselenocyanates [ 27 , 28 , 29 ], selenazo heterocyclic compounds [ 13 , 30 , 31 ], selenoesters [ 32 , 33 , 34 ], selenoureas [ 35 , 36 , 37 , 38 , 39 ], and diselenides [ 19 , 22 , 23 , 24 , 25 , 39 , 40 ]. Additionally, several compounds bearing these functionalities have also been reported to have a potent radical scavenging capacity, allowing the design of molecules with an interesting dual profile as antioxidant and antiproliferative agents [ 19 , 25 , 37 , 38 ].…”