Intermittent low dose irradiation enhances the effectiveness of radio- and chemo-therapy for human colorectal adenocarcinoma cell line HT-29

Abstract

Low dose irradiation (LDIR) induces hormesis and adaptive response in organism and mammalian cell lines. Notably, LDIR generates distinct biological effects in cancer cells from normal cells, e.g., it may affect the growth of cancer cells via the activation of certain cell signaling pathway, which does not exist in normal cells. Therefore, LDIR is considered as a promising assistant method of clinical cancer therapy. In this study, we chose human colorectal adenocarcinoma cell line HT-29 as the experimental model, and investigated the differential biological effects between 250 mGy single dose LDIR and 250 mGy intermittent LDIR pretreatments in high dose irradiation (HDIR) radiotherapy and 5-fluorouracil (5-FU) based chemotherapy. Through the cell growth assays, we observed that 250 mGy intermittent LDIR pretreatment significantly increased the killing effect of both radiotherapy and chemotherapy. Western blotting results showed that intermittent LDIR pretreatment apparently activated the ATM/p53 (ataxia telangiectasia mutated, ATM) pathway in radiotherapy; it also activated ERK and p38MAPK pathways in chemotherapy. When we used chemical inhibitors to block the ATM/p53 or p38MAPK pathways, the intermittent LDIR induced cell growth inhibitions were reversed. However, blockage of ERK pathway could not affect the cell growth inhibiton in chemotherapy. Taken together, our findings evaluated the intermittent LDIR as a potential valuable method that can enhance the effectiveness of radiotherapy and chemotherapy, especially in the radio- or chemo-resistant tumor types.

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

“…The expression of both proteins was clearly correlated with increased cell death, and thus better prognosis [48], suggesting the monitoring of both proteins as robust predictive model of therapeutic response. In line with that observation, Wang et al [49] demonstrated that p38 MAPK, along with ATM/TP53 activation, is required for better outcomes in response to 5-FU combined with low or high dose irradiation. Interestingly, albeit treatments increased both the p38 MAPK and ERK phosphorylated and total proteins, p38 MAPK was the only factor directly involved in the response to RT, as assessed by rescue experiments exploiting MEK (PD98059) or p38 MAPK (SB203580) inhibitors [49].…”

“…In line with that observation, Wang et al [49] demonstrated that p38 MAPK, along with ATM/TP53 activation, is required for better outcomes in response to 5-FU combined with low or high dose irradiation. Interestingly, albeit treatments increased both the p38 MAPK and ERK phosphorylated and total proteins, p38 MAPK was the only factor directly involved in the response to RT, as assessed by rescue experiments exploiting MEK (PD98059) or p38 MAPK (SB203580) inhibitors [49]. Further studies reported 5-FU pre-treatment to radiosensitize CRC cells through p38 MAPK and wt-p53 activation, indicating a cooperativity of either chemotherapy potentiating RT or vice-versa [50] ( Figure 2B).…”

Effect of intermittent low-dose irradiation on the radiotherapy efficiency for MDA-MB-231 human breast adenocarcinoma cell line

“…Wang et al studied the effect of intermittent LDIR on HT29 cells [49]. Their data suggested that the intermittent LDIR noticeably inhibited cell growth in comparison with the HDIR or single LDIR pretreatments.…”

“…Despite the search in valid databases, we found a few articles about the effect of LDIR on p21 expression. Wang reported that the intermittent LDIR increases p21 expression and apoptosis [49], and Li's report showed that p21 expression was reduced after LDIR (750 mGy) without HDIR [53]. In fact, the relationship between the different regimes of LDIR (intermittent and single LDIR) followed by a challenge highdose irradiation (2 Gy) on apoptosis and cell proliferation is not investigated.…”

Influence of Individual Radiosensitivity on the Hormesis Phenomenon: Toward a Mechanistic Explanation Based on the Nucleoshuttling of ATM Protein

“…As a second step, and despite the limitations described above, a small subset of 24 reports involving original human data mentioned in the title or in the abstract was identified. It represents 8.8% and 5.1% of all the inventoried papers, respectively 15 -38 (Tables 1 and 2). By analyzing these reports, 3 major conclusions can be drawn: – There are few original human data about hormesis.…”