The synergistic effects of low-dose irinotecan and TRAIL on TRAIL-resistant HT-29 colon carcinoma in vitro and in vivo

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily that induces apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. However, many tumors remain resistant to treatment with TRAIL. In this study, we investigated the synergistic effects of low-dose irinotecan (CPT-11) and TRAIL on TRAIL‑resistant HT-29 colon carcinoma cells and explored potential mechanisms of apoptosis. Cell viability was analyzed by sulforhodamine B (SRB) assay and apoptosis was evaluated by flow cytometry and DNA ladder assay. The mRNA expression of TRAIL receptors death receptor 4 (DR4) and DR5 were determined by reverse transcription polymerase chain reaction (RT-PCR). The changes of Bax and caspase-9 in protein levels were also detected by western blotting. Tumor growth curves were depicted and tumor inhibitive rates were calculated. Our results showed that the antitumor effect of TRAIL could be enhanced significantly by low-dose CPT-11 on TRAIL-resistant HT-29 cells both in vitro and in vivo. The synergistic apoptotic effect of CPT-11 and TRAIL was proposed to be mediated by upregulating DR5 mRNA expression and increasing expression of Bax and caspase-9 proteins. The data suggest that the combination of TRAIL with low-dose CPT-11 could be an effective therapeutic approach for HT-29 colon carcinoma.

Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis

“…Numerous compounds have been reported to synergistically act with TRAIL to potentiate apoptosis in these cells, including chemotherapeutic drugs and natural compounds. [40][41][42][43][44][45] Our results added the usage of brequinar into this continuously growing list of agents that can be utilized in TRAIL combinatorial therapy. Interestingly, the combined treatment of brequinar and TRAIL did not harm the mammary epithelial cells HMEC suggesting normal cells possess own mechanisms to overcome the sensitization effect.…”

The Synergistic Effects of Low Dose Fluorouracil and TRAIL on TRAIL-Resistant Human Gastric Adenocarcinoma AGS Cells

“…Chemotherapy agents and radiotherapy appear to sensitize cells to the effects of TRAIL [25]. Thus, many tumors resistant to TRAIL-mediated apoptosis when TRAIL is used as a single agent will respond to a combination of conventional chemotherapy or radiotherapy plus TRAIL [5, 32, 33]. …”

“…The cell inhibition rates of TRAIL and 5-Fu were measured by SRB method [5]. Exponentially growing tumor cells were seeded into a 96-well plate (1 × 10 5 /well), and then TRAIL or 5-Fu was added to each well 24 h after incubation, respectively.…”

“…Another receptor, osteoprotegerin (OPG), is a soluble receptor that may play a more prominent role in bone and myeloid cell development [2, 3]. TRAIL induces apoptosis in a wide variety of tumor cells but does not cause toxicity in most normal cells for the large numbers of decoy receptors on normal cells [4, 5]. The in vivo administration of TRAIL has been proved to be safe, unlike the other members of the TNF superfamily [6].…”

“…Thus, TRAIL is a promising cancer therapeutic agent due to its tumor selectivity. However, recent studies showed that many types of cancer cells have intrinsic or acquired resistance to TRAIL-induced apoptosis [5, 7, 8], which potentially restricts its use in treatment. Therefore, for the clinical use of TRAIL in cancer therapy, it is extremely important to overcome TRAIL resistance.…”