Chemotherapeutic multidrug resistance (MDR) is the major hindrance for clinical therapy of colorectal cancer (CRC). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with selective cytotoxicity might overcome MDR of CRC cells. Unfortunately, cross-resistance to TRAIL has been detected in many CRC cells, suggesting the need to combine TRAIL with sensitizers to combat refractory CRC. Our purpose is to explore the potential of combination therapy of TRAIL and tumor-cell targeted photodynamic therapy (PDT) in combating CRC with both chemotherapeutic MDR and TRAIL resistance.
Methods:
Tumor cell-targeted PDT was performed using a Ze-IR700 photosensitizer with high affinity for epidermal growth factor receptor (EGFR). The impact of PDT on the gene expression of CRC cells was revealed by RNA sequencing. The synergistic antitumor effect of long-acting TRAIL and PDT was evaluated in mice bearing tumor grafts of CRC cells with both chemotherapeutic MDR and TRAIL resistance.
Results:
Chemotherapeutic MDR and TRAIL resistance are common in CRC cells. Pretreatment of CRC cells with tumor cell-targeted PDT significantly (10-60 times) increased the sensitivity of these CRC cells to TRAIL by upregulating death receptors. Combination therapy, but not monotherapy, of long-acting TRAIL and PDT greatly induced apoptosis of CRC cells, thus efficiently eradicated large (~150 mm
3
) CRC tumor xenografts in mice.
Conclusions:
Tumor cell-targeted PDT extensively sensitizes CRC cells to TRAIL. Combination therapy of long-acting TRAIL and PDT is promising to combat CRC with both chemotherapeutic MDR and TRAIL resistance, which might be developed as a novel strategy for precision therapy of refractory CRC.
Antibody-based
near-infrared photoimmunotherapy (NIR-PIT) is an
attractive strategy for cancer treatment. Tumor cells can be selectively
and efficiently killed by the targeted delivery of an antibody–photoabsorber
complex followed by exposure to NIR light. Glycoprotein A33 antigen
(GPA33) is highly expressed in most human colorectal cancers (CRCs)
and is an ideal diagnostic and therapeutic target. We previously produced
a single-chain fragment of a variable antibody against GPA33 (A33scFv
antibody). Here, we investigate the efficacy of NIR-PIT by combining
A33scFv with the NIR photoabsorber IR700 (A33scFv-IR700). In vitro, recombinant A33scFv displayed specific binding
and delivery of an NIR dye to GPA33-positive tumor cells. Furthermore,
A33scFv-IR700-mediated NIR-PIT was successful in rapidly and specifically
killing GPA33-positive colorectal tumor cells. NIR-PIT treatment induced
the release of lactate dehydrogenase from tumor cells, followed by
cell necrosis, rather than apoptosis, through the promotion of reactive
oxygen species accumulation in tumor cells. In mice bearing LS174T
tumor grafts, A33scFv selectively accumulated in GPA33-positive tumors.
Following only a single injection of the conjugate and subsequent
illumination, A33scFv-IR700-mediated NIR-PIT induced a significant
increase in therapeutic response in LS174T-tumor mice compared with
that in the non-NIR-PIT groups (p < 0.001). Because
the GPA33 antigen is specifically expressed in CRC tumors, A33scFv-IR700
might be a promising antibody fragment-photoabsorber conjugate for
NIR-PIT of CRC.
Multidrug resistance (MDR), which is common in colorectal cancer (CRC), induces high mortality in patients. Due to its robust and selective apoptosis induction in some CRC cells with MDR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is attractive as a novel tool for CRC therapy. However, TRAIL is limited by its poor tumor-homing ability and inefficient apoptosis induction in CRC cells expressing low levels of death receptor (DR). Here, the tumor-homing RGR peptide (CRGRRST) was fused to TRAIL to produce RGR-TRAIL. Compared with TRAIL, RGR-TRAIL showed greater cell binding and cytotoxicity in CRC cells. In addition, RGR-TRAIL exerted significantly enhanced tumor uptake and growth suppression in mice bearing CRC tumor xenografts. Notably, RGR-TRAIL eradicated all tumor xenografts of DR-overexpressing COLO205 cells. However, TRAIL only showed mild tumor growth suppression under the same conditions, indicating that RGR fusion significantly increased the antitumor effect of TRAIL in DR-overexpressing CRC cells by improving tumor homing. Nevertheless, RGR fusion did not significantly enhance the antitumor effect of TRAIL in HT29 cells expressing low levels of DR. We found that DR expression in HT29 cells was enhanced by epidermal growth factor receptor (EGFR)-targeted photodynamic therapy (PDT). Moreover, both the
in vitro
and
in vivo
antitumor effects of RGR-TRAIL were significantly improved by combination with PDT. HT29 tumor xenografts (∼20%) were even eradicated by combination therapy. These results indicate that it is valuable to further evaluate the combination therapy of RGR-TRAIL and tumor-targeted PDT for clinical therapy of CRC with MDR.
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