Drug Transporter-independent Liver Cancer Cell Killing by a Marine Steroid Methyl Spongoate via Apoptosis Induction

Abstract

Hepatocellular carcinoma (HCC)3 is one of the most common and most aggressive cancers worldwide. The majority of patients have a poor prognosis because of their advanced-stage disease, which is inherently resistant to clinical anticancer drugs, largely because HCC cells express drug transporters, including P-glycoprotein (P-gp), multidrug resistance protein (MRP), and/or breast cancer resistance protein (BCRP) (1-3). Therapy with current anticancer drugs could hardly change the natural history of inoperable HCC (over 80% of HCC cases) (2, 4). Discovery of new types of anticancer drugs, especially those rising superior to drug transporters, is primarily urgent to improve the therapy for HCC.Natural products are extremely important sources of novel anticancer drugs. In fact, over 70% of anticancer drugs have a natural origin (5). The novelty and diversity of chemical structures of natural products give us opportunities to discover potential anticancer candidates with special activities. Several naturally derived drugs in clinical investigation, like salvicine (6 -9) and ecteinascidin 743 (10, 11), show prominent actions in disrupting drug-resistant mechanisms by impairing the expression or functions of drug transporters in tumor cells of acquired multidrug resistance (MDR). These drugs set up a paradigm that guides the discovery of anti-HCC drugs from natural products that can evade or circumvent the mechanisms of intrinsic drug resistance, although not particularly against innate MDR as in liver cancer cells.Steroids are important anticancer drug classes, especially for cancers of sex-related organs such as breast, ovary, and prostate. Those drugs, by mimicking or antagonizing estrogens, prolactin (12), or androgen (13), exert anticancer effect generally in a hormone (receptor)-dependent manner. Such a mode of action limits therapy to the cancers expressing the related hormone receptors or depending on the related hormone signaling pathways. Current steroid anticancer drugs in clinic are mainly synthetic or modified from the related hormones. As anticancer drug candidates, unfortunately, naturally derived steroids, either from land or from the sea, seem to have long been neglected.MESP (cholest-1-en-3-one-20(R)-oic acid methyl ester, Fig. 1A) is a new, marinely derived steroid from the Sanya soft coral Spongodes sp. (14) and has been synthesized (15,16). MESP is a unique steroid because of its rare 21-oic acid methyl ester moiety with 20R configuration (16). Such a uniqueness seems to be translated into its special HCC cell killing in a drug transporterindependent manner, as shown in this study. Although the precise structure-activity relationship remains to be clarified further, MESP provides an important drug lead for HCC therapy.

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

“…6, 7, 17 Tanshinone-1 elicited a more potent cytotoxicity against MDR cells than the respective parental cells with an average RF of 0.83 (Table 1). In contrast, the average RF of adriamycin and vincristine reached 162.7 (Table 1).…”

“…6, 17, 52 The concentration required for 50% inhibition (IC 50 ) of the tested cells was calculated using the Logit method. The RF for each examined drug was calculated as the ratio of the IC 50 value in a MDR subline to that in its parental cell line.…”

Targeting Cellular Proapoptotic Agents from Marine Sources

“…MESP (cholest-1-en-3-one-20(R)-oic acid methyl ester,) is a marinely derived steroid from the Sanya soft coral Spongodes sp and may serve as an important candidate drug lead for Hepatocellular carcinoma therapy. MESP inhibited the phosphorylation of signal transducers and activators of transcription 3 (STAT3), a critical survival signaling factor that reduced the expression of the antiapoptotic protein x-linked inhibitor of apoptosis protein but enhanced the expression of the proapoptotic protein Bax, thus promoting caspase-dependent apoptosis [102].…”

Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells

“…We evaluated the effects of hypoxia (1% O 2 ) on the proliferative inhibition of 3 HCC cell lines by 6 anticancer drugs including sorafenib (the only drug approved for HCC), 5-FU, gemcitabine, cisplatin, adriamycin (these 4 have been tested in clinical trials for HCC) and 6-thioguanine. The 3 tested cell lines (BEL-7402, HepG2 and SMMC-7721) have different expression profiles of important anticancer drug transporters, including P-gp, multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP) [5] . Moreover, the expression of P-gp in HepG2 cells is sensitive to hypoxia and HIF-1 [30] .…”

“…This situation relates to the basic fact that HCC is among the most refractory cancers to anticancer drugs. One likely reason for such drug resistance in HCC could be that HCC cells generally express various drug transporters such as P-glycoprotein (P-gp), which leads to the reduction of cellular drug accumulation [5] . Another possible reason could be that hypoxia occurs extensively in advanced HCC [6][7][8][9] .…”