Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks

Abstract

Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.

Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

“…P-gpexpressing sublines were derived from the corresponding non-P-gp-expressing parental tumor cell lines by selection with different anticancer drugs (2,9,22). We also observed that triptolide nearly equipotently killed human pancreatic cancer Capan-1 and Ewing sarcoma SK-ES-1 cells and PARP inhibitor simmiparibselected resistant variants Capan-1/SP (RF: 0.84) and SK-ES-1/SP (RF: 1.36), and these variants did not express detectable drug transporters, including P-gp, MRP1, or BRCP (data not shown).…”

“…In addition to triptolide, many other natural products, including salvicine (3,4), pseudolaric acid B (5, 6), methyl spongoate, (7) and tanshinone I (2,8), can induce nearly equipotent tumor cell killing in MDR sublines and their respective parental cell lines. A common feature of these agents is that they do not inhibit P-gp drug-efflux function.…”

“…Clinically, few drugs are available that do not produce resistance, and resistancereversal agents are not available because most tested compounds reverse MDR by inhibiting drug transporter function, such as P-glycoprotein (P-gp), which mediates tumor MDR. However, drug transporters are critical for physiologic processes at the blood brain barrier, intestine, kidney, and liver (2).…”

“…We reported that specific compounds can directly kill MDR tumor cells without affecting the function of P-gp, such as the natural products salvicine (3,4), pseudolaric acid B (5, 6), methyl spongoate (7), tanshinone I (2,8), and synthetic small molecules YCH337 (9) and MT series (10)(11)(12). Among them, the MDRovercoming activities of natural products were associated with the regulation of certain transcription factors.…”

Upregulation of Death Receptor 5 and Production of Reactive Oxygen Species Mediate Sensitization of PC-3 Prostate Cancer Cells to TRAIL Induced Apoptosis by Vitisin A

“…It is well documented that ROS plays a critical role in apoptosis induction in several cancers [30][31][32][33] and also ROS mediates TRAIL sensitization through modulation of TRAIL receptor DR5 in prostate cancer cells by several cancer chemopreventive agents such as Orlistat [34], Celastraol [35] and Baicalein [36]. Our flow cytometric analysis revealed that combination of TRAIL and Vitisin A increased the production of ROS and conversely ROS inhibitor NAC blocked the ability of combination of TRAIL and Vitisin A to cleave PARP in PC-3 cells, indicating the role of ROS in apoptotic effect by combination of TRAIL and Vitisin A.…”