Role of Cell Cycle Perturbations in the Combination Therapy of Chemotherapeutic Agents and Radiation

Abstract

The combination of radiotherapy with chemotherapeutic agents that sensitize tumor cells to ionizing radiation has long been regarded as a promising strategy to enhance cancer therapy. Many chemotherapeutic agents interact with radiation and enhance the cytotoxic or anti-tumor effect of radiation through a number of mechanisms. These include an increase in initial radiation damage, inhibition of cellular repair, cell cycle redistribution, enhancement of apoptosis, counteracting hypoxia and overcoming accelerated repopulation. This article focuses on the role of cell cycle perturbations in the radiosensitivity of cancer cells.

Curcumin Enhances the Radiosensitivity of U87 Cells by Inducing DUSP-2 Up-Regulation

“…The resistance in S phase is currently considered to be related to the DNA repair mechanism - homologous recombination in the DNA synthesis phase [3]. DNA repair also contributes to the radiation tolerance by facilitating the formation of repair complexes during the replication process.…”

“…It has been reported that cells in the G2 and M phases are approximately three times more radiosensitive than cells in the S phase of the cell cycle [3], although the exact mechanism for this phenomenon is unknown. These differences can be therapeutically exploited in chemoradiation through cell cycle redistribution strategies, by using either drugs that arrest cells in radiosensitive G2/M phases or drugs that eliminate radioresistant S phase cells [4].…”

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

“…An in vitro study using U87 human glioma cell line showed that 5–10  μ M curcumin could inhibit proliferation and that treated cells were arrested in G2/M stage by increased expression of DUSP-2 and inhibition of ERK and JNK phosphorylation. Interestingly, trapping cells in the G2/M phase appears to enhance their sensitivity to radiation [38, 39]. Curcumin's radiosensitizing effects have also been examined in neuroblastoma (SK-N-MC) cells.…”

Strategies to optimize radiotherapy based on biological responses of tumor and normal tissue

“…1). Specifically, radiobiological responses include: i) molecular reactions such as DSB (14)(15)(16)(17)(18), ATM (19,20), ATR (21), NBS1 (22), BRCA1 (23), DNA-PK (24,25), HIF-1a (26,27), γ-H2AX (28,29), as well as the early response molecules such as Egr-1 (30) and c-fos (31); ii) cellular responses such as apoptosis (32), autophagy (16,(33)(34)(35), cell proliferation rate (36) and changes in cell cycle (37)(38)(39)(40)(41)(42)(43); iii) tissue and organ level responses, including volume changes (44), inflammation, edema and fibrosis (8,45,46); and iv) the overall level of responses, including changes in expression of cytokines such as IL-1 (47), IL-6 (48), TNFα (49) and TGFβ (45). Radiation responses should be considered on multiple, comprehensive levels in the tumor and normal tissue, as well as in the early stage of acute response and the late stage tissue responses.…”