Abstract
TRAIL is considered a promising antitumor agent because it causes apoptosis of transformed cells without affecting normal cells. However, many types of tumors are cytokine resistant, and combination therapy with various chemotherapeutic drugs is being developed to overcome the resistance. We have demonstrated that the combination of TRAIL with doxorubicin, bortezomib, and panobinostat dramatically reduced the viability of TRAIL-resistant A549 and HT-29 cells. Chemotherapy even more efficiently sensitized cells to the DR5-specific mutant variant of TRAIL DR5-B, which does not have an affinity for decoy receptors. Bortezomib and doxorubicin greatly enhanced the surface expression of the death receptors DR5 and DR4, while panobinostat increased expression of DR5 and suppressed expression of DR4 in both cell lines. All drugs increased surface expression of the decoy receptors DcR1 and DcR2. Unlike the combined treatment, if the cells were pretreated with chemotherapy for 24 h, the cytotoxic activity of TRAIL was less pronounced, while sequential treatment of cells enhanced the effectiveness of DR5-B. The same results were obtained with agonistic anti-DR5 antibodies. Thus, the effectiveness of TRAIL was rather limited due to changes in the ratio of death and decoy receptors and DR5-specific agonists may be preferred in combination antitumor therapy regimens.
Highlights
The discovery that the cytokine TRAIL can cause apoptosis of cancer cells without causing the death of normal cells and without showing toxicity in mice and primates, has led to intensive studies on the mechanisms of TRAIL-induced apoptosis
It is known that TRAIL interacts with five receptors, four of which are expressed on the plasma membrane (DR4, DR5, DcR1, DcR2), and the fifth is a soluble osteoprotegerin receptor (OPG) [1]
We examined the effects of chemotherapy such as bortezomib, doxorubicin and panobinostat on the surface expression of TRAIL death and decoy receptors and TRAIL-mediated cell death
Summary
The discovery that the cytokine TRAIL (tumor necrosis factor related apoptosis-inducing ligand) can cause apoptosis of cancer cells without causing the death of normal cells and without showing toxicity in mice and primates, has led to intensive studies on the mechanisms of TRAIL-induced apoptosis. It is known that TRAIL interacts with five receptors, four of which are expressed on the plasma membrane (DR4, DR5, DcR1, DcR2), and the fifth is a soluble osteoprotegerin receptor (OPG) [1]. Death receptors DR4 and DR5 contain the cytoplasmic death domain (DD), which is involved in the initiation of the apoptotic cascade. The binding of TRAIL to DR4 and DR5 causes the association of the FADD (Fas associated protein with death domain) adapter protein and procaspase-8 with the DD domains of death receptors forming DISC (death-inducing signaling complex), followed by activation of caspase-8, which leads to the launch of the apoptotic cascade [2,3]. The other three receptors do not transmit apoptosis signals and can inhibit TRAIL-mediated apoptosis.
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