Maintenance BEZ235 Treatment Prolongs the Therapeutic Effect of the Combination of BEZ235 and Radiotherapy for Colorectal Cancer.

Yu-Hsuan Chen,Yi-Shin Tzeng,Keng-Hsueh Lan,Sung-Hsin Kuo,Ann-Lii Cheng,Ming-Feng Wei,Chun-Wei Wang

doi:10.3390/cancers11081204

Yu-Hsuan Chen, Yi-Shin Tzeng + Show 5 more

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https://doi.org/10.3390/cancers11081204

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Abstract

Our previous study demonstrated that administration of NVP-BEZ235 (BEZ235), a dual PI3K/mTOR inhibitor, before radiotherapy (RT) enhanced the radiotherapeutic effect in colorectal cancer (CRC) cells both in vitro and in vivo. Here, we evaluated whether maintenance BEZ235 treatment, after combinatorial BEZ235 + RT therapy, prolonged the antitumor effect in CRC. K-RAS mutant CRC cells (HCT116 and SW480), wild-type CRC cells (HT29), and HCT116 xenograft tumors were separated into the following six study groups: (1) untreated (control); (2) RT alone; (3) BEZ235 alone; (4) RT + BEZ235; (5) maintenance BEZ235 following RT + BEZ235 (RT + BEZ235 + mBEZ235); and (6) maintenance BEZ235 following BEZ235 (BEZ235 + mBEZ235). RT + BEZ235 + mBEZ235 treatment significantly inhibited cell viability and increased apoptosis in three CRC cell lines compared to the other five treatments in vitro. In the HCT116 xenograft tumor model, RT + BEZ235 + mBEZ235 treatment significantly reduced the tumor size when compared to the other five treatments. Furthermore, the expression of mTOR signaling molecules (p-rpS6 and p-eIF4E), DNA double-strand break (DSB) repair-related molecules (p-ATM and p-DNA-PKcs), and angiogenesis-related molecules (VEGF-A and HIF-1α) was significantly downregulated after RT + BEZ235 + mBEZ235 treatment both in vitro and in vivo when compared to the RT + BEZ235, RT, BEZ235, BEZ235 + mBEZ235, and control treatments. Cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), 53BP1, and γ-H2AX expression in the HCT116 xenograft tissue and three CRC cell lines were significantly upregulated after RT + BEZ235 + mBEZ235 treatment. Maintenance BEZ235 treatment in CRC cells prolonged the inhibition of cell viability, enhancement of apoptosis, attenuation of mTOR signaling, impairment of the DNA-DSB repair mechanism, and downregulation of angiogenesis that occurred due to concurrent BEZ235 and RT treatment.

Highlights

Preoperative radiotherapy (RT) is used to reduce the risk of local recurrence and improve survival in patients with locally advanced rectal cancer [1,2,3]
HCT116, HT29, 1000 cells seeded per well, we found that RT + BEZ235 treatment followed by BEZ235 maintenance or
These findings suggest that RT + BEZ235 + mBEZ235 treatment caused increased apoptosis when compared to RT + BEZ235 treatment in all colorectal cancer (CRC) cell lines

Summary

Introduction

Preoperative radiotherapy (RT) is used to reduce the risk of local recurrence and improve survival in patients with locally advanced rectal cancer [1,2,3]. Adding chemotherapy to RT in the neoadjuvant setting for locally advanced rectal cancer provides superior local control and a higher anal preservation rate as well as less treatment-related toxicity when compared with postoperative concurrent chemoradiotherapy (CCRT) [4,5]. Randomized trials have reported that, in addition to conventional long-course RT, hypofractionated short-course RT (5 Gy × 5 fractions) followed immediately by the operation is another option for locally advanced rectal cancer [6,7]. In two ongoing randomized trials comparing different treatment regimens for neoadjuvant short-course RT in patients with rectal cancer, more satisfactory pathological complete remission (pCR) rates and clinical outcomes have been observed in patients undergoing systemic chemotherapy following short-course RT than in those not undergoing systemic chemotherapy [8,9]

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