Abstract
Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.
Highlights
Colorectal cancer (CRC) represents the third deadliest malignancy in the West[1]
High oxaliplatin levels suppress the growth of colorectal cancer and noncancerous cells without excellent selectivity
The results showed that oxaliplatin reduced viability in HCT-116, LoVo, and noncancerous GES-1 cells with IC50 values of 18.5, 21.5, and 27.6 μM, respectively (Fig. 1a)
Summary
Colorectal cancer (CRC) represents the third deadliest malignancy in the West[1]. The only curative treatment is surgical resection. Timely diagnosis is difficult, as early signs are either unspecific or insignificant. The majority of colorectal malignancy cases are detected at advanced stages. Treatment prognosis in early-stage CRC is generally quite promising, with an ~90% cure rate, which drops to below 10% in patients with advanced-stage CRC. Targeted chemotherapy and chemotherapy are frequently used in CRC management, and known to improve long-term survival and reduce recurrence. Conventional chemotherapy, on the other hand, has a limited effect and causes detrimental side effects to patients, due to a lack of specificity. A new drug or method is necessary for improving prognosis
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