Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells.
ABSTRACT Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.
Article: Plant polyphenols and tumors: from mechanisms to therapies, prevention, and protection against toxicity of anti-cancer treatments.[show abstract] [hide abstract]
ABSTRACT: Polyphenolic molecules produced by higher plants in response to biotic and abiotic stresses exert numerous effects on tumorigenic cell transformation, and on tumor cells in vitro and in vivo, and may interact with conventional anti-tumor therapies. In the present review, we collected and critically discussed data on: (i) redox-dependent and redox-independent mechanisms underlying cytotoxic/cytostatic effects of PPs and their metabolites towards tumor cells and cytoprotection of normal cells; (ii) mechanisms of anti-angiogenic and anti-metastatic action of PPs; (iii) PPs-associated phototoxicity against tumor cells and photoprotection of non-tumor cells; (iv) PPs effects on drug-metabolizing enzymes as a basis for their synergism or antagonism with chemotherapy; (v) molecular pathways leading to tumor chemoprevention by PPs; and (vi) PPs as protectors against toxic effects of chemo-, radio-, and photodynamic therapies.Current Medicinal Chemistry 09/2009; 16(30):3943-65. · 4.86 Impact Factor