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  • br of CD or vWF positive areas


    of CD31- or vWF-positive areas per field was markedly decreased in the tumor tissues treated with oxaliplatin or CPT-11 alone, and in combi-nation with BP10A (Fig. 6C). These data suggest that BP10A also sy-nergistically suppress the progression of angiogenesis with anti-cancer drugs for CRC. It has been shown to potentially enhance the therapeutic indices of different class anticancer agents in vivo.
    4. Discussion
    In this study, BP10A was suggested as a novel formula with a potent anticancer effect as well as synergistic effect with chemotherapeutic agents for CRC. BP10A is a novel herbal prescription that is composed of two plant materials, D. sophia seeds and P. praeruptorum roots in equal weights. Several studies have reported that the constituents de-rived from the ethanol extract of D. sophia seeds exhibit a significant cytotoxicity towards human cancer cell lines and an anti-inflammatory activity [15,17,26]. Additionally, phytochemical and pharmacological studies also have shown that the constituents from the ethanol extract of P. praeruptorum roots have modulatory effects on cancer cells such as anti-inflammatory, chemopreventive, and multi drug resistance re-versal activities [19–22,27].
    In this study, first, we confirmed the phytochemical constituents and their quantity in the BP10A extract to guarantee the quality of the other batches used in our experiments using the UPLC system. The five constituents, isoquercitrin, isorhamnetin-3-o-β-glucopyranoside,
    (+)-praeruptorin A, B and E were identified as analytical markers of BP10A. Among them, isoquercitrin has been known to be cytotoxic against various cancer cells such as colon [28], pancreatic [29], and Benazepril [30,31] cancer cells. Previously, we showed that helveticoside and quercetin isolated from D. sophia seeds, exerted cytotoxic effects in various human cancer cells [15]. It has also been reported that praer-uptorin A and B have the anticancer activity through the inhibition of cell invasion in human cervical cancer cells [31,32]. The others are not known yet about anticancer-related activity. Therefore, the antitumor activities of BP10A might be caused by the synergistic efficacy of the composing constituents of BP10A. The action mechanism of each con-stituent should be elucidated in the future study. 
    Next, we used two colorectal cancer cell lines, HCT-116 and KM12SM, to evaluate the in vitro antitumor efficacy of BP10A. Treatment of BP10A induced the dose dependent cytotoxicity, apop-totic activity such as degradation of PARP and caspase activity, and the cell cycle arrest at G2/M phase through the regulation of G2/M checkpoint proteins expression in HCT-116 and KM12SM cells. These results collectively indicate that BP10A exerted the cytotoxic potential by inducing the apoptosis and the cell cycle arrest at G2/M in colorectal cancer cells. Furthermore, BP10A act synergistically with two cancer drugs widely used for colorectal cancer treatment, oxaliplatin and CPT-11, enhancing the cytotoxic effect of these drugs in vitro.
    PDTX models remarkably resemble the pathophysiology of human tumors in respect of high fidelity in mutational status, transcriptome, histology, polymorphism and copy number variation. Therefore, PDTX has become the most realistic model for preclinical studies for the va-lidation of potential therapeutic targets to develop antic-cancer drugs [33]. Recently, PDTX models from various tumors have been estab-lished, such as CRC, breast cancer, and renal cell carcinoma [34–36]. In this study, the antitumor activity of BP10A and chemotherapeutic cancer drugs for CRC were evaluated in 3 colon PDTX models (45 F, 102 F and 115 F) which showed similar histologic architecture and pathologic characteristics to those of the original tumors [23,37]. The evaluation of the antitumor activity in the three PDTX models revealed that BP10A as well as oxaliplatin and CPT-11 that are frequently pre-scribed to CRC patients, significantly suppress the tumor growth. Our data indicate that these PDTX models are a good system for evaluating the efficacy of antitumor reagents.