Resiniferatoxin induces death of bladder cancer cells associated with mitochondrial dysfunction and reduces tumor growth in a xenograft mouse model

Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9‐Epipolygodial against Drug‐Resistant Cancer Cells

“…Given the considerable interest in the medicinal chemistry community toward the exploitation of TRPV1-targeting agents as anti-nociceptives 14-18,21-24 and the cytotoxicity associated with some of the studied compounds, 27-32 these findings could be significant.…”

“…Indeed, it is puzzling why both TRPV1 agonists 29-32 and antagonists 29,30 administered independently would exert antiproliferatve effects against cancer cells through similar cell death mechanisms. 29,68 It remains to be established whether there exist additional functionally different intracellular targets possessing structural requirements for binding similar to those at the vanilloid site on TRPV1.…”

“…[20][21][22][23][24] Furtherr esearch has shown that in addition to its expression in sensory neurons and involvement in different modalities of pain, TRPV1 is also upregulated in various human cancerc ells, [25][26][27] and its activation in humang lioma cells leads to endoplasmic reticulum stress followed by cell death. [28] TRPV1 thus appears to be ap romisingt arget for cancerd rug development, and there are many reports of studies investigating TRPV1 ligands, such as the TRPV1 agonists capsaicin [29][30][31] and resiniferatoxin, [27,32] as well as the TRPV1 antagonists capsazepine [29,30] and SB366791, [29] as potentiala nticancer agents. However,t he results of mechanistic studies have complicated matters by questioning whether the anticancere ffects of vanilloids are mediated by TRPV1,a nd have revealed that TRPV1 antagonists generally do not prevent vanilloid agonist-induced cell death.…”

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

“…Although many reports investigating vanilloid agonists as potential anticancer agents have appeared in the literature, the involvement of TRPV1 in mediating their antiproliferative effects has been questioned on many occasions as vanilloid antagonists have consistently failed to prevent capsaicin or RTX-induced cell death [33–37]. In the related publication [55], we show that these observations also apply to α,β-unsaturated 1,4-dialdehyde terpenoids, such as 1 and 9-epipolygodial, and that cancer cell death induced by these compounds cannot be explained by TRPV1-targeting.…”

“…It has thus been proposed to be a an attractive target for the treatment of brain tumors [32], as it was shown that its activation with endogenous agonists leads to endoplasmic reticulum (ER) stress in human glioma cells, followed by cell death [32]. Many reports investigating TRPV1-targeting agents such as capsaicin [33–36], resiniferatoxin [33,37], capsazepine [34,35], and SB366791 [34], as potential anticancer agents, have appeared in the literature. Curiously, however, the group of α,β-unsaturated 1,4-dialdehyde terpenoids (Figure 1), studied for many diverse biological properties [38] and known for their TRPV1 agonistic activities [38–43] have not been studied as anticancer agents.…”