ITF2357 (Givinostat) br The overall response rate of chemoth
The overall response rate of chemotherapeutic chemical drugs for CRC such as 5-fluorouracil, oxaliplatin and CPT-11 has a very narrow therapeutic window because of their severe toxicity . Therefore, a potential way to improve the therapeutic eﬃcacy and limit their ad-verse eﬀects is a combination therapy. Moreover, because the combi-nation of two or more anti-cancer drugs enhances the over eﬃcacy compared to monotherapy and simultaneously reduces the metastatic potential, currently, combination therapy has become a cornerstone of cancer therapy [38,39]. Recently, phytochemicals such as curcuminoids and quercetin were shown to commonly have antioxidant, antitumor,
and anti-inflammatory eﬀects, and when they are used in combination with a chemotherapeutic cancer drug, the enhanced antitumor eﬀects and reduced adverse side eﬀects were observed [40–42]. We, therefore, hypothesized that the combination therapy of BP10A with chemical drugs, such as oxaliplatin or CPT-11, can improve the antitumor ac-tivity of chemotherapy. In this study, BP10A alone showed a similar therapeutic eﬃcacy compared to that of oxaliplatin or CPT-11, while its combination with oxaliplatin or CPT-11 showed a remarkable en-hancement of the antitumor eﬃcacy of oxaliplatin or CPT-11. It was interesting that BP10A showed a potent antitumor activity as well as synergistic antitumor eﬀect with CPT-11 even on patient derived tumor that showed a relative resistance to CPT-11 such as 45 F. Treatment of CPT-11 in combination with BP10A completely suppressed the tumor growth in both the tumor volumes and weights, and the tumors in these xenograft models remained at their initial size or even showed shrinkage in the tumor volumes. Moreover, the ITF2357 (Givinostat) of angio-genesis-associated factors (CD31 or vWF) was significantly down-regulated in BP10A and CPT-11 or BP10A and oxaliplatin co-treatment, suggesting an enhanced inhibition of tumor angiogenesis. Collectively, these results support that BP10A could improve the therapeutic eﬃcacy of the conventional chemotherapeutic chemical drugs for colon cancer, CPT-11 or oxaliplatin, and the three colon cancer xenografts used in this study are very useful PDTX models for the evaluation of non-clin-ical antitumor eﬃcacy. However, it is need to further in-depth non-clinical and clinical studies to demonstrate the eﬀectiveness of BP10A for the development of anti-cancer drugs, whether it taken as a stan-dalone or combination treatment for the colorectal cancer patient.
The present study showed that BP10A, an ethanol extract consisting of two medicinal herbs, could induce cytotoxicity through causing the apoptosis and growth arrest in colon cancer cells, and suppress the tumor growth of patient-derived colon cancer xenografts. Moreover, BP10A had a potential synergistic eﬀect on tumor growth inhibition with the conventional anti-cancer drugs, oxaliplatin or CPT-11, for colorectal cancer. Therefore, BP10A can be considered a candidate substance for the herbal medicine development of anti-cancer drugs for the colorectal cancer patients.
Conflict of interest
The authors declare that there is no conflict of interests regarding the publication of this paper.
Appendix A. Supplementary data
 Y. Pommier, Drugging topoisomerases: lessons and challenges, ACS Chem. Biol. 8
 Y.Y. Xiong, J.S. Wang, F.H. Wu, J. Li, L.Y. Kong, The eﬀects of (+/-)-praeruptorin A on airway inflammation, remodeling and transforming growth factor-beta1/Smad signaling pathway in a murine model of allergic asthma, Int. Immunopharmacol. 14
 T. Liang, W. Yue, Q. Li, Chemopreventive eﬀects of Peucedanum praeruptorum DUNN and its major constituents on SGC7901 gastric cancer cells, Molecules 15
 P.J. Yu, H. Jin, J.Y. Zhang, G.F. Wang, J.R. Li, Z.G. Zhu, Y.X. Tian, S.Y. Wu, W. Xu, J.J. Zhang, S.G. Wu, Pyranocoumarins isolated from Peucedanum praeruptorum dunn suppress lipopolysaccharide-induced inflammatory response in murine mac-rophages through inhibition of NF-kappaB and STAT3 activation, Inflammation 35