Further insights in the antiproliferative activity of cardenolides from the aerial parts of Pergularia tomentosa

Pergularia tomentosa (Asclepiadaceae) is a milkweed tropical plant used in traditional medicine for the treatment of several diseases such as bronchitis, constipation and skin diseases [1]-[3]. Previously we reported the occurrence of cardiac glycosides with trans fused A/B rings of the steroidal skeleton and with a single sugar, linked to the 2α- and 3β-positions of the aglycone by hemiketal and acetal functions respectively [1],[3],[4]. Isolated cardenolides inhibited cell viability of PC3, Hela, Calu-1, MCF-7, and U251MG cell lines exhibiting IC₅₀ values ranging from 0.2 to 8.0 μM [4]. Herein, the ability of the isolated compounds to inhibit cell viability of Hepg2 (liver hepatocellular carcinoma) cell line has been evaluated. Of all tested compounds, calotropin and calactin showed the highest activity with IC₅₀ values of 0.83 µM and 0.11 µM, respectively. Chemically, these compounds differ in the stereochemistry of C-3ʹ of the sugar linked to the aglycone. With the aim to deeper explore their ability to inhibit cancer progression, the effects on cellular migration and proliferation were also investigated. Our results showed that calotropin and calactin at 1μM inhibited cell migration (wound healing assay) and proliferation (fase S entry) of the Hepg2 cancer cell line. They induced apoptosis associated with activation of caspase-3 and increased p53 expression, more than 35% and 45%, respectively, when compared with staurosporine used as positive control. Moreover reduction of GRP78, a general ER-stress marker was also observed. These findings suggest that selected compounds from P. tomentosa are potential leads to be explored as anti-cancer agents.

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• References

• 1 Hamed AI, Plaza A, Balestrieri ML, Mahalel UA, Springuel IV, Oleszek W. etal. Cardenolide glycosides from Pergularia tomentosa and their proapoptotic activity in Kaposi’s sarcoma cells. J Nat Prod 2006; 69: 1319-1322
• 2 Al-Said MS, Abu-Jayyab A, Hifnawy MS. Biochemical studies on ghalakinoside a possible antitumor agent from Pergularia tomentosa. J Ethnopharmacol 1989; 27: 235-240
• 3 Piacente S, Masullo M, De Neve N, Dewelle J, Hamed A, Kiss R. et al. Cardenolides from Pergularia tomentosa Display Cytotoxic Activity Resulting from Their Potent Inhibition of Na+/K+-ATPase. J Nat Prod 2009; 72: 1087-1091
• 4 Hosseini SH, Masullo M, Cerulli A, Martucciello S, Ayyari M, Pizza C. Antiproliferative Cardenolides from the Aerial Parts of Pergularia tomentosa . J Nat Prod 2019; 82: 74-79