Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

Abstract

Abstract. Oxaliplatin (OX) has been widely used in adjuvant and palliative treatments of advanced colon cancer; however, cancer cells ultimately become resistant in the majority of cases. Therefore, the development of a novel strategy to overcome this resistance is important for the effective treatment of colon cancer. Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer; therefore, the present study used murine CT26 colon carcinoma cells to explore whether inhibition of autophagy by 3-methyladenine (3-MA) is able to enhance OX-induced apoptosis in vitro and OX-suppressed tumor growth in vivo. CT26 cells were treated with 3-MA, OX, or 3-MA plus OX, and the autophagy, apoptosis and proliferation of the CT26 cells was investigated. Additionally, the therapeutic efficiency of the combination of 3-MA and OX treatment was evaluated in vivo by determining the survival time of the tumor-bearing mice and, thus, tumor growth rate. The treatment of CT26 cells in vitro with OX alone increased autophagy as well as apoptosis, whereas treatment with 3-MA plus OX markedly inhibited OX-induced autophagy, but increased OX-induced cell apoptosis. Furthermore, the combination of OX and 3-MA treatment significantly suppressed tumor growth in vivo and prolonged mouse survival time when compared with OX treatment alone. Similarly, 3-MA increased OX-induced cell apoptosis and decreased autophagy in xenograft tumor tissues. Thus, the administration of 3-MA may increase tumor cell sensitivity to OX by reducing its autophagic effects and enhancing its apoptotic effects. Data obtained in the present study indicates that the clinical combination of an autophagy inhibitor with OX may increase the therapeutic effect of OX and improve the clinical outcome of patients with colon cancer.

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

“…It is a third-generation platinum-based anti-neoplastic agent commonly used in the treatment of CRC (15,16). Oxaliplatin application in the clinic has brought about notable improvements in the response rate and progression-free survival in advanced colon cancer, but ~40% of patients still develop resistance (3,17). Resistance generation limits oxaliplatin application in the course of clinical treatment.…”

“…Although comprehensive strategies in the treatment of CRC have been developed for a number of years, the five-year survival rate of metastatic colon cancer is only 10% (3). In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival.…”

“…In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival. Nevertheless, more than 40% of patients still develop significant resistance (3,4). Therefore, how to overcome resistance to oxaliplatin is a key scientific problem to be solved in the treatment of metastatic colon cancers.…”

Gap junction composed of connexin43 modulates 5-fluorouracil, oxaliplatin and irinotecan resistance on colorectal cancers

“…For example, 5-FU, which has been used for many years, has a single agent effective rate of 24% (2). Although oxaliplatin improves the response rate of patients in advanced colon cancer, >40% patients develop serious resistance (6). Resistance to irinotecan, as a first-line therapy for metastatic colon cancer in combination with other antitumor agents, has also been reported in recent years (7).…”

Single nucleotide polymorphisms in glutathione S-transferase P1 and M1 genes and overall survival of patients with ovarian serous cystadenocarcinoma treated with chemotherapy

“…Patients with ovarian cancer are generally treated with first-line chemotherapy, including paclitaxel and platinum-based drugs (4). Cisplatin, the first-generation platinum-based drug, was gradually replaced by carboplatin and oxaliplatin, which are second-and third-generation platinum-based drugs, respectively (5,6). Cisplatin was replaced due to liver and kidney toxicity, in addition to side effects such as mucositis, neutropenia and alopecia.…”