Abstract
We try to elucidate whether a carbon ion beam alone or in combination with gemcitabine has advantages over X-ray in targeting putative pancreatic cancer stem-like cells (CSCs) in vitro and in vivo. Colony, spheroid formation and tumorigenicity assays confirmed that CD44+/ESA+ cells sorted from PANC1 and PK45 cells have more CSC properties than CD44-/ESA- cells. The number of colonies and spheroids formed from CSCs after carbon ion beam irradiation was significantly reduced compared to after X-ray irradiation, and they were extremely highly suppressed when carbon ion beam combined with gemcitabine. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.23-2.66. Expressions of multiple cell death-related genes were remarkably highly induced, and large numbers of γH2AX foci in CSCs were formed after carbon ion beam combined with gemcitabine. The highly expressed CSC markers were significantly inhibited after 30 Gy of carbon ion beam and almost lost after 25 Gy carbon ion beam combined with 50 mg/kg gemcitabine. In conclusion, a carbon ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs via irreparable clustered DSB compared to a carbon ion alone or X-rays combined with gemcitabine.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), which constitutes more than 90% of pancreatic cancers in humans, is the fourth most frequent cause of cancerrelated death world-wide [1, 2] and is characterized by a high rate of metastasis with high resistance to chemoradiotherapy [3, 4]
Aliquots of 500 CD44+/ESA+ cells isolated from PK45, PNAC1 were transplanted subcutaneously into the right lower thigh of immunodeficient SCID mice and 5 x 103 CD44-/ESA- cells were transplanted subcutaneously into the left lower thigh (Figure 1C)
Our data suggested that CD44+/ESA+/CD24+, CD44+/ESA+ cells isolated from PK45, PNAC1 cells present the characteristics of cancer stemlike cells (CSCs)
Summary
Pancreatic ductal adenocarcinoma (PDAC), which constitutes more than 90% of pancreatic cancers in humans, is the fourth most frequent cause of cancerrelated death world-wide [1, 2] and is characterized by a high rate of metastasis with high resistance to chemoradiotherapy [3, 4]. In spite of great efforts to improve medical and surgical care over the past decades, little substantial progress has been made towards improving the PDAC prognosis, with the average overall 5-year survival rate still less than 5% [5, 6]. It has been reported that chemotherapy combined with conventional radiotherapy for locally advanced pancreatic cancer achieved about 1725% of 2 year overall survival [7,8,9]. Resistance to chemo-radiotherapy is a major cause of treatment failure in pancreatic cancer. There is a strong need for new therapeutic strategies targeting PDAC’s chemoradioresistant cells to elevate overall survival
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