|Santos, Felipe -|
|Latorre, Andreia -|
|Hueza, Isis -|
|Sanches, Daniel -|
|Lippi, Luciana -|
|Spinosa, Helenice -|
Submitted to: Phytomedicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 9, 2011
Publication Date: September 15, 2011
Citation: Santos, F.M., Latorre, A.O., Hueza, I.M., Sanches, D.S., Lippi, L.L., Gardner, D.R., Spinosa, H.S. 2011. Increased antitumor efficacy by the combined administration of swainsonine and cisplatin in vivo. Phytomedicine. 18(12):1096-1101. Interpretive Summary: Swainsonine is the toxin found in several poisonous plants of international interest. Its toxicity results from the inhibition of several key processes in cellar metabolism. In addition, swainsonine is of interest for use in cancer treatment mostly as an adjuvant in certain chemotherapies. In this study, swainsonine was investigated as to its affects on the sensitivity of test cancer cells to treatment with cisplatin, a platinum-based chemotherapeutic. A mouse and cancer cell model was tested by treatment with swainsonine and/or cisplatin two days after transplantation with the selected cancer cells. The results showed a greater reduction in the cell fluid volume in mice from the cisplatin + swainsonine (63.5%) than in mice from the cisplatin group (45.7%), an elevated induction of cancer cell death by cisplatin + swainsonine treatment when compared to cisplatin alone, and an increase in the median survival from 12.5 days observed in the untreated control group, 15 days for the cisplatin group to 27 days in the cisplatin + swainsonine group. Overall, the results indicate that swainsonine increases the sensitivity of tested cancer cells to cisplatin and an increased antitumor efficacy by their combined administration.
Technical Abstract: Swainsonine is a natural alpha-mannosidase inhibitor found in numerous poisonous plants, such as Astragalus lentiginosus. Its mechanism of action is through the inhibition of Golgi alpha-mannosidase II activity in the N-glycan biosynthesis pathway. As a result, swainsonine inhibits the production of complex ß1,6-branched N-linked glycans, which are related to the malignant phenotype of tumor cells. In this study, we investigated whether treatment with swainsonine affects the sensitivity of Ehrlich ascites carcinoma (EAC) cells to cisplatin. To this end, male C57BL/6 mice were treated with swainsonine (SW – 0.5 mg/kg, i.p., twice-daily for ten days) and/or cisplatin (Cis – 0.25 mg/kg, i.p., every other day for a total of five applications) two days after transplantation with EAC cells. The results showed a greater reduction in the ascites volume in mice from the CisSW group (63.5%) than in mice from the Cis group (45.7%), an elevated induction of apoptosis by CisSW treatment when compared to Cis alone, as demonstrated by higher percentage of cells in the subG1 phase in that group (p < 0.0001 Kruskal–Wallis, p < 0.0001 control vs. CisSW, p < 0.001 Co vs. Cis post-test Dunn), and an increase in the median survival from 12.5 days observed in the control group to 27 days in the CisSW group, which corresponds to a 116% survival increase (p = 0.0022 Co vs. CisSW Log rank test). In addition, the mice from the Cis group had a median survival of only 15 days, an increase of just 20% compared to controls. Our results indicate that swainsonine increases the sensitivity of EAC cells to cisplatin.