Toad Venom Antiproliferative Activities on Metastatic Melanoma: Bio-Guided Fractionation and Screening of the Compounds of Two Different Venoms

Abstract

Melanoma is the most common cancer in young adults, with a constantly increasing incidence. Metastatic melanoma is a very aggressive cancer with a 5-year survival rate of about 22−25%. This is, in most cases, due to a lack of therapies which are effective on the long term. Hence, it is crucial to find new therapeutic agents to increase patient survival. Toad venoms are a rich source of potentially pharmaceutically active compounds and studies have highlighted their possible effect on cancer cells. We focused on the venoms of two different toad species: Bufo bufo and Rhinella marina. We screened the venom crude extracts, the fractions from crude extracts and isolated biomolecules by studying their antiproliferative properties on melanoma cells aiming to determine the compound or the combination of compounds with the highest antiproliferative effect. Our results indicated strong antiproliferative capacities of toad venoms on melanoma cells. We found that these effects were mainly due to bufadienolides that are cardiotonic steroids potentially acting on the Na+/K+ ATPase pump which is overexpressed in melanoma. Finally, our results indicated that bufalin alone was the most interesting compound among the isolated bufadienolides because it had the highest antiproliferative activity on melanoma cells.

The Parotoid Gland Secretion from Peruvian Toad Rhinella horribilis (Wiegmann, 1833): Chemical Composition and Effect on the Proliferation and Migration of Lung Cancer Cells

“…Several studies on the composition of PGS have been undertaken with the methanol soluble fraction of the crude venom. Recently, the effect was reported of PGS of Bufo bufo and R. marina on metastatic melanoma, finding that the bufadienolide bufalin was the best antiproliferative agent in the samples [53]. Sinhorin, et al [54] described the composition of the Amazonian Rhinella margaritifera PGS and reported argininyl diacids, bufotalin, and cinobufagin argininyl diacids as well as the bufadienolides bufotalin, cinobufagin, and telocinobufagin as main compounds.…”

Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

“…While many studies have demonstrated that Fli1 is a pro-cancer factor [ 68 , 69 ], CS including MBG are becoming attractive anti-cancer drug candidates [ 70 , 71 ]. It is generally accepted that PE is associated with a low risk of cancer, which is not surprising considering that endogenous levels of MBG and other CS are dramatically increased in PE patients [ 27 , 28 ] and therefore suppress the growth of tumors in vivo and in vitro [ 72 , 73 , 74 ]. Therefore, theoretically, in cancer patients and experimental animals, MBG should suppress the levels of Fli1, an oncogene.…”

Preeclampsia: Сardiotonic Steroids, Fibrosis and a Hint to Cancerogenesis

“…While many studies demonstrate that Fli1 is a pro-cancer factor [57,58], CS, including MBG, are becoming attractive anticancer drugs [59,60]. It is generally accepted that PE is associated with a low risk of cancer, which is not surprising considering that endogenous levels of MBG and other CS are dramatically increased in PE patients [27,28] and therefore suppress the growth of tumors in vivo and in vitro [61,62,63]. Therefore, theoretically, in cancer, patients and experimental animals, MBG should suppress levels of Fli1, an oncogene.…”

“…Proscillaridin A was identified as a potential treatment compound with IC50 values ranging from 0.007 μM to 0.55 μM in various tumor types [87]. Importantly, the number of studies in which bufadienolides were used as an in-vitro anti-cancer treatment is heightened, and bufadienolide inhibitors of the Na/K-ATPase are used in vitro and in vivo include MBG [59,60], bufalin [88,89], cinobufagin [90], resibufagenin [91], proscillaridin A [92], gamabufotalin [93], and 1α,2α-Epoxyscillirosidine [94]. Analyzing experiments and clinical data it is obvious that MBG and other Na/K-ATPase inhibitors hold promise to treat cancer, and following anti-CS antibody treatment to PE patients we must expect a rise of Fli1 and be alert.…”