Cellular Response to Chemoradiotherapy, Radiotherapy and Chemotherapy in Two Colorectal Cancer Cell Lines

Abstract

The cellular response to chemoradiotherapy was investigated in cells of the HCT116 (wild-type TP53) and HT29 (mutated TP53) human colorectal cancer cell lines to better understand how the chemotherapeutic agent 5-fluorouracil (5-FU) acts as a radiosensitizer in vitro and how it contributes to the well-documented greater efficacy of chemoradiotherapy compared to radiotherapy (or chemotherapy) alone. A bolus 5-FU treatment protocol that simulated actual clinical clearance kinetics was used with a radiation dose given within 90 min after drug addition. The involvements of key signaling pathways (DNA damage response, cell cycle progression, cell proliferation, cell death) in cell responses were investigated concurrently, allowing for direct correlations of numerous treatment response phenotypes. Early DNA damage response, substantial cell death, loss of clonogenicity, and senescence characterized both radiotherapy- and chemoradiotherapy-treated cultures but not chemotherapy-treated cultures. The largest G(2)/M arrests and strongest correlation of senescence with non-clonogenicity were seen in radiotherapy- and chemoradiotherapy-treated HCT116 cell cultures, suggesting that functional TP53 could play a role in maintaining/inducing these cellular phenotypes. Overall, chemoradiotherapy proved to be the most effective treatment modality since it resulted in the strongest growth inhibitions, largest G(2)/M arrests, largest fractions of senescent cells, and complete loss of clonogenicity in both cell lines.

Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells

“…Indeed, the aim of these therapies are cancer growth inhibition. 26,27 One of the most effective methods in efficient radiation therapy is combining it with chemotherapy, to improve the cytotoxicity against cancer cells. In addition, when cancerous cells are radiation-resistant, the combination of chemotherapy with this method can increase treatment response.…”

“…In addition, when cancerous cells are radiation-resistant, the combination of chemotherapy with this method can increase treatment response. 22,27 Therefore, radiotherapy with a new chemotherapy drug is expected to reduce complications of chemotherapy and increase the treatment outcome.…”

“…31 With the purpose of overcoming resistance in CRC therapies, the study of new treatments options is essential to recognize effective treatments including combinatorial treatments. 22,27 Consequently, in this study, the anti-cancer effects of irinotecan as the conventional chemotherapeutic agent, in comparison with 17-AAG as possible radiosensitizers, in the CRC cell line were investigated.…”

Zerumbone increases oxidative stress in a thiol‐dependent ROS‐independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation

“…In this study, we investigated whether sesquiterpene zerumbone from edible ginger could enhance the radiosensitivity of CRC cells in vitro. We first assessed the stand‐alone toxicity of zerumbone in CRC cells and chose the radiosensitive, most sensitive to zerumbone HCT116 cells (wild‐type p53; mutant k‐RAS ) and radioresistant, least sensitive to zerumbone HT29 cells (mutant p53; wild‐type k‐RAS ) for further investigations. Although both cell lines were used to study the mechanism of zerumbone‐mediated radiosensitization, the effect on cell cycle/apoptosis and DNA repair were studied in HCT116 cells, but not in HT29 cells for two reasons: (1) zerumbone treatment in HCT116 cells, but not in HT29 cells reduced the “shoulder” region of the radiation survival curve, which indicated inhibition of sub‐lethal DNA damage repair as one of the prominent mechanism of action, and (2) “shoulderless” cell survival curves are also indicative of cells in late G2/M phase of the cell cycle .…”

Radiosensitization of human breast cancer cells to ultraviolet light by 5-fluorouracil

“…Chemotherapy is reported to radiosensitize various types of tumors, and may improve the outcome of cancer radiotherapy (12,13). Multiple mechanisms appear to be involved in the radiosensitization of tumor cells by chemotherapy, such as the potentiation of radiation damage (base damage, DNA single-and doublestrand breaks), the inhibition of post-irradiation DNA repair, the redistribution of the cell cycle, and the augmentation of apoptosis (14,15).…”