Antitumor and antiangiogenic effects of Tonantzitlolone B, an uncommon diterpene from Stillingia loranthacea

Abstract

Natural products have played a pivotal role for the discovery of anticancer drugs. Tonantzitlolones are flexibilan-type diterpenes rare in nature; therefore, few reports have shown antiviral and cytotoxic activities. This study aimed to investigate the in vivo antitumor action of Tonantzitlolone B (TNZ-B) and its toxicity. Toxicity was evaluated in mice (acute and micronucleus assays). Antitumor activity of TNZ-B (1.5 or 3 mg/kg intraperitoneally -i.p.) was assessed in Ehrlich ascites carcinoma model. Angiogenesis and reactive oxygen species (ROS) and nitric oxide (NO) production were also investigated, in addition to toxicological effects after 7-day treatment. The LD 50 (lethal dose 50%) was estimated at around 25 mg/kg (i.p.), and no genotoxicity was recorded. TNZ-B reduced the Ehrlich tumor's volume and total viable cancer cell count (p < 0.001 for both). Additionally, TNZ-B reduced peritumoral microvessel density (p < 0.01), suggesting antiangiogenic action. Moreover, a decrease was observed on ROS (p < 0.05) and nitric oxide (p < 0.001) levels. No significant clinical findings were observed in the analysis of biochemical, hematological, and histological (liver and kidney) parameters. In conclusion, TNZ-B exerts antitumor and antiangiogenic effects by reducing ROS and NO levels and has weak in vivo dose-repeated toxicity. These data contribute to elucidate the antitumor action of TNZ-B and point the way for further studies with this natural compound as an anticancer drug.

AaLaeA targets AaFla1 to mediate the production of antitumor compound in Alternaria alstroemeria

“…Some compounds with antitumor activity were found to be significantly upregulated (Table 3). Quercetin [32], strychnopentamine [33], gitogenin [34], rhodioloside [35], liensinine [36], l ‐selenomethionine [37], compactin [38], tonantzitlolone b [39], ginsenoside rg2 [40], campesterol [41], pristimerin derivative [42], cinobufagin [43], and anisomycin [44] have been shown to have antitumor activity. Among them, quercetin, a flavonoid, was the most significantly upregulated.…”

“…In contrast, overexpression of Fla1 caused a significant increment in the antitumor activity of the strain, with a reduction in IC 50 from 445 μg/mL to 368 μg/mL and a significant 7‐fold increment in apoptosis. Antitumor‐related compounds have been reported to accumulate in Fla1 overexpressing transformants, for example, quercetin [32], strychnopentamine [33], gitogenin [34], rhodioloside [35], liensinine [36], l ‐selenomethionine [37], compactin [38], tonantzitlolone b [39], ginsenoside rg2 [40], campesterol [41], pristimerin derivative [42], cinobufagin [43] and anisomycin [44], with the flavonoid quercetin being the most significantly upregulated. This result is in contrast to the significant reduction in flavonoid content of AaLaeA OE26 , which also confirms in terms of compound accumulation that AaFla1 is negatively regulated by AaLaeA, and therefore affecting the antitumor activity of the strain.…”

Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms

“…Arg. [229,230]. Tonantzitlolone has been known to have antiproliferative properties against certain cancer cell lines and possess antitumor activity [229,230].…”

“…[229,230]. Tonantzitlolone has been known to have antiproliferative properties against certain cancer cell lines and possess antitumor activity [229,230]. Sourbier et al [110] investigated cytotoxicity targets and mechanisms of action of tonantzitlolone in clear cell RCC.…”