Abstract
An ideal cancer therapy specifically targets cancer cells while sparing normal tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) elicits apoptosis by engaging its cognate death receptors (DRs—namely, DR4 and DR5. The cancer cell-selective proapoptotic action of TRAIL is highly attractive for cancer therapy, but clinical application of TRAIL is rather limited due to tumors’ inherent or acquired TRAIL resistance. Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL-induced apoptosis. Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers. In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese). Research from our laboratories and others have revealed the synergy of a tanshinones-TRAIL combination in diverse types of cancer cells through up-regulation of DR5 and/or down-regulation of antiapoptotic proteins such as survivin. Thus, in addition to their anticancer mechanisms, tanshinones as TRAIL sensitizers hold great potential to be translated to TRAIL-based therapeutic modalities for combatting cancer.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which benefits from its malignant cell-selective proapoptotic action, is an ideal cancer therapeutic agent, but its potential is ironically sabotaged by either intrinsic or acquired resistance commonly developed by tumor cells
As for the TRAIL-sensitizing mechanisms of tanshinones, it appears that reactive oxygen species (ROS)-mediated DR5 up-regulation is the primary modes of action
It would be informative to decipher additional targets of TRAIL resistance mechanisms likely modulated by tanshinones in the context of various types of tumor cells, as a detailed molecular understanding of tanshinones-elicited TRAIL sensitization would allow for a rational design for more effective tanshinones-TRAIL synergy
Summary
Despite advances in developing new therapeutic modalities for cancer, chemotherapy is still the fundamental tool for cancer treatment primarily through induction of apoptosis in cancer cells. We summarize the anticancer potential of tanshinones, the bioactive components isolated from the dried root of the medicinal plant Salvia miltiorrhiza Bunge (Lamiaceae) (a.k.a. Danshen) (Figure 1) that has been frequently used in traditional Chinese medicine for over a thousand years to prevent or treat various conditions including menstrual disorders, hepatitis, and cardiovascular diseases [4, 5]. We focus on the recently discovered role of tanshinones as sensitizing agents of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which has an attractive anticancer potential due to its cancer cell-selective proapoptotic action but is often limited by the development of TRAIL-resistance in many human tumors. The mechanisms whereby tanshinones overcome TRAIL resistance and the potential translation of tanshinones to TRAIL-based cancer remedies are discussed
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