Therapeutic Efficacy and Inhibitory Mechanism of Regorafenib Combined With Radiation in Colorectal Cancer

Abstract

Background: Although both chemotherapy and radiotherapy (RT) can sufficiently maintain tumor suppression of colorectal cancer (CRC), these treatments may trigger the expression of nuclear factor kappa B (NF-ĸB) and compromise patients' survival. Regorafenib suppresses NF-ĸB activity in various tumor types. However, whether regorafenib may act as a suitable radiosensitizer to enhance therapeutic efficacy of RT remains unknown. Materials and Methods: Here, we established a CRC-bearing animal model to investigate the therapeutic efficacy of regorafenib in combination with RT, through measurement of tumor growth, body weight, whole-body computed tomography (CT) scan and immunohisto-chemistry staining. Results: Smallest tumor size and weight were found in the combination treatment group. In addition, RT-induced upregulation of NF-ĸB and downstream proteins were diminished by regorafenib. Moreover, the body weight and liver pathology in the treated group were similar to those of the non-treated control group. Conclusion: Regorafenib may enhance the anti-CRC efficacy of RT.Recent innovative radiotherapy (RT) technologies, including intensity-modulated RT, image-guided RT, volumetric-modulated arc therapy, intraoperative RT, and stereotactic body RT (SBRT), are widely used to treat many types of cancer (1-3). RT as neoadjuvant strategy offers therapeutic benefits for patients with colorectal cancer (CRC). The combination of RT and surgical resection or chemotherapy has been shown to reduce the local recurrence rate and improve the survival of patients with CRC (4, 5). For increasing anti-CRC efficacy of RT, novel radiosensitizers that sensitize cancer cells to radiation have been developed (6).

Modulation of the Tumor Microenvironment by Microbiota-Derived Short-Chain Fatty Acids: Impact in Colorectal Cancer Therapy

“…A large number of studies have enlightened the antitumorigenic properties of colon microbiota-derived SCFAs and their effects in CRC cells [ 2 , 6 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Additionally, as described in this review, they can modulate the tumor microenvironment in many distinct ways.…”

“…This drug is normally used with FOLFIRI to treat metastatic CRC when the cancer continues to progress during or after other treatments. Another available biological drug is regorafenib (Stivarga) that acts as a multi-kinase inhibitor, namely through the inactivation of angiogenic and oncogenic kinases, such as VEGF 1–3, fibroblast growth factor receptor 1, EGFR, RAF, and tyrosine-protein kinase [ 18 , 20 ]. It is designed to treat patients with metastatic colon cancer whose cancer has continued to advance after approved standard therapies [ 18 , 20 ].…”

Regorafenib alone or in combination with high/low-dose radiotherapy plus toripalimab as third-line treatment in patients with metastatic colorectal cancer: protocol for a prospective, randomized, controlled phase II clinical trial (SLOT)

“…Besides synergizing with ICIs, regorafenib may also enhance the radiosensitivity of colorectal tumors by blocking radiation-induced activation of receptor tyrosine kinases, inhibiting VEGF-mediated angiogenesis, and suppressing DNA damage repair ( 17 , 18 ). However, only a few studies have demonstrated these effects of regorafenib using tumor cell lines and mouse models, and no clinical trials investigating regorafenib in combination with radiotherapy have been reported.…”

Amentoflavone induces caspase‐dependent/−independent apoptosis and dysregulates cyclin‐dependent kinase‐mediated cell cycle in colorectal cancer in vitro and in vivo

“…The mice were anesthetized with 1%–3% isoflurane during computerized tomography scanning on Days 0 and 10 of treatment. The operation parameters of tube energy were 55 kVp × 145 μA, and the scanning resolution was 145 × 145 × 145 μm with 360 projections of direction 28 …”

“…The operation parameters of tube energy were 55 kVp  145 μA, and the scanning resolution was 145  145  145 μm with 360 projections of direction. 28…”