Platonin induces autophagy-associated cell death in human leukemia cells

Abstract

Platonin is a photosensitizer used for photodynamic therapy. In this study, we tested the effect of platonin on human leukemic cells. Treatment with platonin in the dark markedly reduced cell membrane integrity, and induced significant G 0 /G 1 arrest of a panel of human leukemic cell lines, including U937, HL-60, K562, NB4 and THP-1. Development of hypodiploid cells was not evident in these cell lines within 24 h, but was noted in U937, HL-60 and NB4 cells after 24 h. No myeloid differentiation of these cells was noted after five-day treatment. Intriguingly, exposure of monoblastic U937 cells to platonin caused changes characteristic of autophagy, including appearance of cytoplasmic membranous vacuoles and formation of acidic vesicular organelles (AVO) in more than 95% of cells. The platonin-induced autophagy was accompanied by localization of microtubule-associated protein 1 light chain 3 to autophagosomes. Pretreatment with pancaspase inhibitor Z-VAD-fmk abrogated the platonin-induced hypodiploidity, but had no effect on growth inhibition and formation of AVO, indicating a caspase-independent autophagy-associated cell death. Pretreatment of cells with 3-methyladenine attenuated platonin-mediated growth inhibition and formation of AVO. Platonin augmented the expression of BNIP3 in both U937 and K562 cells, whereas had an opposite effect on phosphorylation of mTOR downstream molecule p70S6K. Platonin, at the condition inducing autophagy, induced the mitochondrial membrane permeation. These results suggest that the platonin is capable of inhibiting growth as well as inducing cell death, mainly autophagy-associated, in leukemic cells via a mitochondria-mediated and caspase-independent pathway. A markedly less viability inhibition was noted to human monocytes, the normal counterpart of these myeloid leukemic cells. Platonin, other than a photodynamic agent, may offer significant promise as a therapeutic agent against leukemia.

Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling

“…39,40 Accumulating anticancer agents have been documented to trigger the cellular autophagic process, but the role that autophagy plays in cancer chemotherapy is still controversial. Certain anticancer agents i.e., polyoxomolybdates-, platonin-or phenethyl isothiocyanate could induce autophagic cell death to enhance chemotherapeutic efficacy, [41][42][43] while others, i.e., suberoylanilide hydroxamic acid, arginine deiminase or timosaponin A-III mediated protective autophagy that antagonized apoptotic cell death. [31][32][33] In this study, we demonstrated that quercetin triggered autophagy in human gastric cancer cells both in vitro and in vivo.…”

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

“…In animal cells, the components required for these phases are regulated by extracellular growth factors, and they are found mainly in the two gap phases, G 1 (between M and [25] . Platonin has been reported to induce significant G 0 /G 1 arrest of a panel of human leukemic cell lines, including U937, HL-60, K562, NB4, and THP-1 [16] . In this study, we also found that the loss of the proliferative capacity of VSMCs that had been treated with platonin is associated with cells that have been arrested in the S and G 2 /M phases.…”

“…The anti-inflammatory mechanisms of platonin may be due to the suppression of MAPKs, nuclear factor (NF)-κB, and activator protein (AP)-1 [15] . Recently, platonin was also reported to be capable of inhibiting cell growth and inducing extensive autophagyassociated cell death in leukemic cells [16] .…”

Role of autophagy in the progression and suppression of leukemias

“…Glucocorticoids such as dexamethasone also contributed to autophagic death in leukemia of lymphoid origin [85,86]. In addition to these compounds, platonin, a photosensitizing compounds used in photodynamic therapy, was also found to induce cell death in several leukemic cell lines independent of the caspase pathway as is characteristic of autophagy [87]. In another study, autophagy was shown to be an important mechanism for cell death due to extensive recycling of cellular organelles damaged from photodynamic therapy in mouse lymphocytic leukemia cells [88].…”