Phenalenone‐photodynamic therapy induces apoptosis on human tumor cells mediated by caspase‐8 and p38‐MAPK activation

Abstract

Photodynamic therapy (PDT) is a rising and hopeful treatment for solid tumors and others malignancies. PDT uses harmless visible light to activate a tumor-associated photosensitizer (PS). The excited PS generates cytotoxic reactive oxygen species (ROS) that induce damage and death of tumor cells. It is known that certain phytoalexins and phytoanticipins derived from plants often display a PS-like activity due to a phenalenone (PN) moiety-an efficient singlet oxygen photosensitizer-in its skeleton. The aim of this study is to explore the phototoxic properties of PN on the human cell line tumor-derived HL60 (acute promyelocytic leukemia) and to identify the cell-specific targets of ROS involved in the tumor cell death. Our results reveal that PN acts as an excellent PS, showing a potent antitumor cell activity in presence of light. PN-PDT generates intracellular ROS, via oxidation reaction mechanisms type I and II, resulting in an induction of apoptosis. Moreover, both extrinsic (through direct activation of caspase-3) and intrinsic (through mitochondrial depolarization) pathways of apoptosis are induced by PN-PDT. Using pharmacologic inhibitors, we also find that PN-PDT activates caspase-8/tBid and p38-MAPK, triggering the activation of the apoptotic pathways. Although, survival pathways are also promoted through PI3 K/Akt and JNK activation, the net result of PN-PDT is the tumor cell death. The present work identifies to PN, for the first time, as a potent photosensitizer in human tumor cell lines and proposes a mechanism by which ROS induces apoptosis of tumor cell.

An Activatable Photosensitizer Targeting Human NAD(P)H: Quinone Oxidoreductase 1

“…Our probe consists of the quinone substrate covalently linked via central amide bond to the PS, phenalenone (PN). PN exhibits a high singlet oxygen quantum yield (≈1) and has good photostability in aqueous solution . Moreover, its electronic framework is similar to previously used fluorophores, and so we hypothesized its singlet oxygen production would be quenched by the nearby electron‐deficient quinone via photon‐induced electron‐transfer (PeT) mechanism .…”

“…PN exhibits ah igh singlet oxygen quantum yield ( % 1) andh as good photostability in aqueous solution. [39][40][41][42] Moreover,i ts electronic framework is similart op reviously used fluorophores, and so we hypothesized its singleto xygen production would be quenched by the nearbye lectron-deficient quinone via photon-induced electron-transfer (PeT) mechanism. [22] Upon hNQO1-mediated reduction, the quinol product is expected to initiate intramolecular cyclization at the central amide carbonyl carbon, producing dihydrocoumarin and releasing native PN ( Figure 1 The synthesis of the hNQO1 probe entailed two parts:f irst, quinone propanoic acid (Q3PA) was preparedf rom commercially available trimethylhydroquinone and methyl-3-methyl-2butenoate in methanesulfonic acid, with addition of N-bromosuccinimide to facilitate ring opening( SchemeS1, Supporting Information).…”

Sulphur doped carbon dots enhance photodynamic therapy via PI3K/Akt signalling pathway

“…Among these, p38 and JNK, members of MAPKs, which closely related to the induction of apoptosis, 34 can directly regulate the translocation of Bax and the process of anti‐apoptotic proteins phosphorylation respectively 35,36 . The activation of p38 and JNK has been frequently observed in response to PDT, followed by inducing phosphorylation of Bcl‐2 family proteins and elicits MOMP 37‐39 . PI3K/Akt is one of the most frequently activated signalling networks during tumorigenesis.…”

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

“…These compounds could induce apoptosis-like through the mitochondrial pathway initiated by ROS production. Therefore, our proposal is that withanolides-type compounds could induce the formation of ROS, leading this excessive ROS to trigger apoptosis-like death by altering the mitochondrial membrane potential and damaging the respiratory chain, as has been proven in a human leukemia cell line [25].…”