<p>Salinomycin and Sulforaphane Exerted Synergistic Antiproliferative and Proapoptotic Effects on Colorectal Cancer Cells by Inhibiting the PI3K/Akt Signaling Pathway in vitro and in vivo</p>

Abstract

Background: Both salinomycin (SAL) and sulforaphane (SFN) exert their antitumorigenic effects in various types of cancer We investigated whether combining salinomycin (SAL, an antibiotic ionophore) with sulforaphane (SFN, a phytochemical) exerted synergistic antiproliferative and proapoptotic activities in colorectal cancer (CRC) cells in vitro and in vivo by evaluating the proliferative and apoptotic responses of two CRC cell lines. Materials and Methods: The combination index (CI) was calculated using the Chou-Talalay method, and the effects of the synergistic combination (CI<1) of lower doses of SAL and SFN were selected for further studies. Anti-tumor effect of the combination of SAL and SFN was tested both in vitro and in vivo. Results: Cotreatment effectively inhibited proliferation, migration and invasion and enhanced apoptosis. The xenograft model also showed similar results. Furthermore, we evaluated the molecular mechanism behind SAL-and SFN-mediated CRC cell apoptosis. The combination treatment induced apoptosis in Caco-2 and CX-1 cells by inhibiting the PI3K/Akt pathway, which increased the expression of the tumor suppressor protein p53. The treatment also decreased the expression of the survival protein Bcl-2 and increased the expression of the proapoptotic protein Bax, which increased the Bax/Bcl-2 ratio, as well as enhanced poly ADP-ribose polymerase (PARP) cleavage. Upon inhibiting the PI3K/Akt pathway with LY294002 prior to cotreatment, we detected enhanced PARP cleavage compared to that in the cotreatment only group. Conclusion: We investigated whether the combination of SAL and SFN had antiproliferative and proapoptotic effects in CRC cells both in vitro and in vivo. Cotreatment also significantly decreased migration and invasion compared to that of the control and SAL or SFN monotherapies. This novel combination of SAL and SFN might provide a potential strategy to treat CRC.

Nanodelivery of natural isothiocyanates as a cancer therapeutic

“…Similar results were also seen in the xenograft model. In the combination therapy, decreased expression of PI3K, p-Akt and Bcl-2 and increased expression of Bax, p53 and cleaved PARP suggests PI3K/Akt pathway is involved in synergistic effect of SAL and SFN induced apoptosis [96]. Synergistic effects of SFN were also observed in triple combination therapy.…”

Organosulfur Compounds in Colorectal Cancer Prevention and Progression

“…Sulforaphane treatment has even been shown to prevent angiogenesis and migration at a concentration of 12.5 µM by inhibiting HIF-1a and VEGF [ 68 ]. Finally, sulforaphane has been demonstrated to be cytoprotective of healthy colon cells [ 47 ] and to increase the efficacy of other chemotherapeutic agents such as PR-104A (2.5 µM sulforaphane and PR-104A at all concentrations), 5 fluorouracil (7.1 µM of 5 fluorouracil with 5.8 µM sulforaphane derivative), and salinomycin (5 µM salinomycin with 10 µM sulforaphane) ( Table 1 ) [ 69 , 70 , 71 ]. Sulforaphane at a concentration of 10 µM has also been shown to increase the effectiveness of folinic acid (FOLFOX) against cancer cell lines, but it also increased the expression of multidrug resistance protein 2 (MRP2), meaning that it may reduce the activity of some other chemotherapeutic agents due to their expulsion from the cell [ 72 ].…”

“…Adding to the in vitro investigations, numerous in vivo studies in murine models have further confirmed sulforaphane’s efficacy in colorectal cancer treatment and prevention. Two recent studies tested sulforaphane’s efficacy against primary CRC cell cultures and Caco-2 cells, and then confirmed their positive in vitro results by testing sulforaphane treatment against xenografts derived from the same primary cells in SCID/nude mice [ 64 , 70 ]. Both studies found that the treatment significantly reduced the size of the xenografts compared with controls, with one study observing a 70% reduction in xenograft size with daily intraperitoneal injections of 0.08 µmoles of sulforaphane ( Table 1 ) [ 64 ].…”

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

“…Sulforaphane could significantly sensitize human breast, lung, colorectal, and bladder cancer cells to variant chemotherapeutic agents via downregulation of NF-kB, induction of cell cycle arrest, and reduction of cyclin A and p-Akt (424)(425)(426)(427). Furthermore, sulforaphane increased the in vitro and in vivo antiproliferative activity of salinomycin in colorectal cancer cells via diminished signaling of the PI3K/Akt pathway (428). Moreover, shikonin reversed gemcitabine tolerance in a xenograft model of pancreatic cancer via modulation of the NF-kB signaling pathway (429).…”