P7 peptides targeting bFGF sensitize colorectal cancer cells to CPT-11

Abstract

Abstract. The low survival rate of patients with colorectal cancer (CRC) is mainly due to the drug resistance of tumor cells to chemotherapeutic agents. It has been reported that basic fibroblast growth factor (bFGF) is an essential factor involved in the epigenetic mechanisms of drug resistance, which provides a novel potential target for improving the sensitivity of tumor cells to chemotherapeutic agents. In this study, we first demonstrate that a novel bFGF antagonist, peptide P7, previously isolated by phage display technology, reversed bFGF-induced resistance to irinotecan hydrochloride (CPT-11), and counteracted the anti-apoptotic effects of bFGF on CPT-11-treated HT-29 cells. Further experiments indicated that the inhibition of Akt activation, the suppression of bFGF internalization, the increase in the Bax to Bcl-2 ratio and the downregulation of cytokeratin 8 (CK8) by P7 may contribute to the counteracting of the anti-apoptotic effects of bFGF, and further reversal of bFGF-induced resistance to CPT-11. Our results suggest that peptide P7 may have therapeutic potential in CRC as a sensitizer to chemotherapeutic agents by targeting bFGF. IntroductionColorectal cancer (CRC) is the fourth most common malignant tumor worldwide, leading to approximately 200,000 deaths per year in Europe and the US (1). Although improved surgical techniques combined with multi-disciplinary approaches have been applied in therapy, the 5-year survival rate for patients with CRC remains poor, mainly due to tumor cells acquiring multidrug resistance properties. The overexpression of drug efflux proteins (2-4) is considered a common mechanism of multidrug resistance, as shown in preclinical studies. However, no significant improvement in the chemotherapeutic effectiveness has been observed in clinical practice by the inhibition of drug efflux proteins (5,6), suggesting the existence of other chemoresistance mechanisms.Irinotecan hydrochloride (CPT-11) is a water-soluble derivative of camptothecin (7), presenting a wide spectrum of antitumor activity by preventing DNA religation, resulting in DNA double-strand breaks and eventually leading to apoptosis (8). The cytotoxic activity of CPT-11 has been reported in several malignant tumors, including breast, lung, ovarian, and colon cancer (9-16). CPT-11 serving as a DNA topoisomerase I inhibitor, combined with 5-fluorouracil (5-FU) and leucovorin has been accepted as a first-line treatment for patients with advanced CRC. However, this combination only offers a 2-month median survival advantage over previous chemotherapeutic agents (8). Any treatment conferring a modest survival benefit for CRC will have significant meaning. Understanding the mechanisms of drug resistance will greatly contribute to the development of more effective treatments for improving survival in patients with CRC.Basic fibroblast growth factor (bFGF) is a pleiotropic factor involved in the processes of cell proliferation, differentiation and anti-apoptosis in a wide variety of cells derived from the mesoderm and ne...

Leukaemia inhibitory factor is associated with treatment resistance in oesophageal adenocarcinoma

“…Anti-bFGF antibodies were shown to enhance radiosensitivity in oesophageal SCC through a reduction in colony formation in-vitro [ 36 ]. In addition, targeting of bFGF by a peptide has been shown to improve chemo-sensitivity in CRC [ 43 ]. These findings in the literature and within our study show that LIF and bFGF together both play important roles in cancer progression and treatment response in many cancers and may influence both OAC cells and host immunity by functioning as part of the active cytokine network.…”

Role of Basic Fibroblast Growth Factor in Cancer: Biological Activity, Targeted Therapies, and Prognostic Value

“…Moreover, as disclosed by Samie and colleagues, ascorbic acid treatment substantially reduced the expression of bFGF, bFGFR, PDGF, PDGFR, and PLC- γ in the HT29 cell line [ 101 ]. The low survival rate of CRC patients is principally due to the chemotherapeutic resistance of tumor cells; relatedly, it has been reported that bFGF could regulate the epigenetic mechanisms of drug resistance, thus representing a novel potential target for improving the sensitivity of tumor cells to chemotherapeutic agents [ 102 ]. According to preclinical findings, clinical studies confirmed bFGF as a clinicopathological factor and highlighted its possible role as a marker of metastatic progression and patient prognosis [ 103 , 104 ].…”