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Sanguisorba officinalis L synergistically enhanced 5-fluorouracil cytotoxicity in colorectal cancer cells by promoting a reactive oxygen species-mediated, mitochondria-caspase-dependent apoptotic pathway

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ABSTRACT

Sanguisorba officinalis L. radix is a widely used herb called DiYu (DY) in China and has an extensive range of bioactivities, including anti-cancer, anti-inflammatory, and anti-oxidative activities. However, there is little evidence to support its anti-cancer effects against colorectal cancer (CRC). The first-line chemotherapeutic agent 5-fluorouracil (5-FU) is used to treat CRC, but its efficiency is hampered by acquired drug resistance. This study found that a water extract of DY exerted anti-proliferative effects against two CRC cell lines (HCT-116 and RKO), and it sensitized CRC cells to 5-FU therapy by activating a reactive oxygen species (ROS)-mediated, mitochondria-caspase-dependent apoptotic pathway. Co-treatment of DY and 5-FU significantly elevated ROS levels, up-regulated Bax/Bcl-2 ratio and triggered mitochondrial dysfunction, followed by a release of cytochrome c and up-regulation of proteins such as cleaved-caspase-9/3 and cleaved-PARP. Additionally, the induction of autophagy may be involved in mediating synergism of DY in HCT-116 cells. Gallic acid (GA), catechinic acid (CA) and ellagic acid (EA) were identified as the potential chief constituents responsible for the synergistic effects of DY. In conclusion, co-treatment of DY, specifically GA, CA and EA, with 5-FU may be a potential alternative therapeutic strategy for CRC by enhancing an intrinsic apoptotic pathway.

No MeSH data available.


A schematic diagram of a ROS-mediated, mitochondria-caspase-dependent apoptosis involved in mediating the synergistic anti-proliferative effects of DY/tannins and 5-FU against CRC.DY and 5-FU synergistically promoted the generation of ROS in CRC cells and triggered a mitochondria disruption (cytochrome c release) by boosting the ratio of Bax/Bcl-2, which then activated caspase-9/3 and PARP. A combination of GA, CA and EA exhibited comparable synergistic effects on 5-FU cytotoxicity to DY water extract, but the underlying mechanism needs to be explored.
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f7: A schematic diagram of a ROS-mediated, mitochondria-caspase-dependent apoptosis involved in mediating the synergistic anti-proliferative effects of DY/tannins and 5-FU against CRC.DY and 5-FU synergistically promoted the generation of ROS in CRC cells and triggered a mitochondria disruption (cytochrome c release) by boosting the ratio of Bax/Bcl-2, which then activated caspase-9/3 and PARP. A combination of GA, CA and EA exhibited comparable synergistic effects on 5-FU cytotoxicity to DY water extract, but the underlying mechanism needs to be explored.

Mentions: In conclusion, a water extract of DY was first found to have anti-proliferative activity against CRC cells. In addition, DY sensitized CRC cells to 5-FU therapy and alleviated the cytotoxicity of 5-FU on normal cells. A mechanistic study revealed that a ROS-mediated, mitochondria-caspase-dependent apoptotic pathway is possibly involved in the synergism. For HCT-116 cells, autophagy induced by DY may also help to enhance the cytotoxicity of 5-FU. Moreover, a combination of three tannins in DY, namely GA, CA and EA, was comparable to the overall DY extract in mediating the synergistic cytotoxicity with 5-FU, suggesting a promising combination therapy strategy for 5-FU-resistant CRC. These findings (Fig. 7) should be confirmed in drug-resistant CRC cells and, most importantly, in vivo; these studies are currently in progress.


Sanguisorba officinalis L synergistically enhanced 5-fluorouracil cytotoxicity in colorectal cancer cells by promoting a reactive oxygen species-mediated, mitochondria-caspase-dependent apoptotic pathway
A schematic diagram of a ROS-mediated, mitochondria-caspase-dependent apoptosis involved in mediating the synergistic anti-proliferative effects of DY/tannins and 5-FU against CRC.DY and 5-FU synergistically promoted the generation of ROS in CRC cells and triggered a mitochondria disruption (cytochrome c release) by boosting the ratio of Bax/Bcl-2, which then activated caspase-9/3 and PARP. A combination of GA, CA and EA exhibited comparable synergistic effects on 5-FU cytotoxicity to DY water extract, but the underlying mechanism needs to be explored.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037464&req=5

f7: A schematic diagram of a ROS-mediated, mitochondria-caspase-dependent apoptosis involved in mediating the synergistic anti-proliferative effects of DY/tannins and 5-FU against CRC.DY and 5-FU synergistically promoted the generation of ROS in CRC cells and triggered a mitochondria disruption (cytochrome c release) by boosting the ratio of Bax/Bcl-2, which then activated caspase-9/3 and PARP. A combination of GA, CA and EA exhibited comparable synergistic effects on 5-FU cytotoxicity to DY water extract, but the underlying mechanism needs to be explored.
Mentions: In conclusion, a water extract of DY was first found to have anti-proliferative activity against CRC cells. In addition, DY sensitized CRC cells to 5-FU therapy and alleviated the cytotoxicity of 5-FU on normal cells. A mechanistic study revealed that a ROS-mediated, mitochondria-caspase-dependent apoptotic pathway is possibly involved in the synergism. For HCT-116 cells, autophagy induced by DY may also help to enhance the cytotoxicity of 5-FU. Moreover, a combination of three tannins in DY, namely GA, CA and EA, was comparable to the overall DY extract in mediating the synergistic cytotoxicity with 5-FU, suggesting a promising combination therapy strategy for 5-FU-resistant CRC. These findings (Fig. 7) should be confirmed in drug-resistant CRC cells and, most importantly, in vivo; these studies are currently in progress.

View Article: PubMed Central - PubMed

ABSTRACT

Sanguisorba officinalis L. radix is a widely used herb called DiYu (DY) in China and has an extensive range of bioactivities, including anti-cancer, anti-inflammatory, and anti-oxidative activities. However, there is little evidence to support its anti-cancer effects against colorectal cancer (CRC). The first-line chemotherapeutic agent 5-fluorouracil (5-FU) is used to treat CRC, but its efficiency is hampered by acquired drug resistance. This study found that a water extract of DY exerted anti-proliferative effects against two CRC cell lines (HCT-116 and RKO), and it sensitized CRC cells to 5-FU therapy by activating a reactive oxygen species (ROS)-mediated, mitochondria-caspase-dependent apoptotic pathway. Co-treatment of DY and 5-FU significantly elevated ROS levels, up-regulated Bax/Bcl-2 ratio and triggered mitochondrial dysfunction, followed by a release of cytochrome c and up-regulation of proteins such as cleaved-caspase-9/3 and cleaved-PARP. Additionally, the induction of autophagy may be involved in mediating synergism of DY in HCT-116 cells. Gallic acid (GA), catechinic acid (CA) and ellagic acid (EA) were identified as the potential chief constituents responsible for the synergistic effects of DY. In conclusion, co-treatment of DY, specifically GA, CA and EA, with 5-FU may be a potential alternative therapeutic strategy for CRC by enhancing an intrinsic apoptotic pathway.

No MeSH data available.