Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer

Kim, Bo Ram; Jeong, Yoon-Su; Jo, Min Jee; Park, Seong Hye; Na, Yoo Jin; Kim, Jung Lim; Jeong, Soyeon; Yun, Ho-Gyeong; Kang, Seongwon; Lee, Dong Hoon; Oh, Sang Cheul

doi:10.1158/1535-7163.mct-18-0196

Cited by 17 publications

(8 citation statements)

References 50 publications

(51 reference statements)

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“…IHC was carried out as previously described [41]. The tissue was observed by confocal microscopy (ZEISS-LSM 700, ZEISS, Oberkochen, Germany).…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

Jeong

Kim

et al. 2019

Cancers

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Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed. The purpose of this study was to determine the effect of cannabidiol (CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells. We established oxaliplatin-resistant cell lines, DLD-1 R and colo205 R, in CRC DLD-1 and colo205 cells. Autophagic cell death was induced when oxaliplatin-resistant cells were treated with both oxaliplatin and CBD. Additionally, phosphorylation of nitric oxide synthase 3 (NOS3) was increased in oxaliplatin-resistant cells compared to that in parent cells. Combined treatment with oxaliplatin and CBD reduced phospho-NOS3 levels and nitric oxide (NO) production and resulted in the production of reactive oxygen species (ROS) by reducing the levels of superoxide dismutase 2, an antioxidant present in the mitochondria, causing mitochondrial dysfunction. Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance.

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“…IHC was carried out as previously described [41]. The tissue was observed by confocal microscopy (ZEISS-LSM 700, ZEISS, Oberkochen, Germany).…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

Jeong

Kim

et al. 2019

Cancers

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“…Genipin (GP) is an alternative to currently used chemical- and physical-based collagen crosslinking agents. GP is a naturally occurring organic crosslinking agent derived from gardenia plant (Gardenia jasminoides), which has been used in Chinese medicine for its anti-carcinogenic, anti-angiogenic, and neuroprotective properties [ 41 , 42 , 43 , 44 ]. Compared to other chemical crosslinking agents, GP has many advantages including being a natural crosslinking agent, the stability and biocompatibility of the crosslinked products, and low toxicity [ 45 , 46 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold

Shortridge

Fakhrabadi

Wuescher

et al. 2021

IJMS

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The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation and providing a sustained release of anti-inflammatory cytokine from the scaffold in the digestive inflammatory environment are predicated upon a comprehensive understanding of three fundamental questions. (1) How does the release rate of cytokine from the scaffold change in the digestive inflammatory environment? (2) Can we prevent the premature scaffold degradation and burst release of the loaded cytokine in the digestive inflammatory environment? (3) How does the scaffold degradation prevention technique affect the immunomodulatory capacity of the scaffold? This study investigated the impacts of the digestive inflammatory environment on scaffold degradation and how pre-mature degradation can be prevented using genipin crosslinking and how genipin crosslinking affects the interleukin-4 (IL-4) release from the scaffold and differentiation of naïve macrophages (M0). Our results demonstrated that the digestive inflammatory environment (DIE) attenuates protein retention within the scaffold. Over 14 days, the encapsulated protein released 46% more in DIE than in phosphate buffer saline (PBS), which was improved through genipin crosslinking. We have identified the 0.5 (w/v) genipin concentration as an optimal concentration for improved IL-4 released from the scaffold, cell viability, mechanical strength, and scaffold porosity, and immunomodulation studies. The IL-4 released from the injectable scaffold could differentiate naïve macrophages to an anti-inflammatory (M2) lineage; however, upon genipin crosslinking, the immunomodulatory capacity of the scaffold diminished significantly, and pro-inflammatory markers were expressed dominantly.

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“…Our previous study, we found that genipin enhanced oxaliplatin-induced apoptosis in colorectal cancer 22. In our study, we investigated whether genipin enhanced oxaliplatin induced cell death for gastric cancer.…”

Section: Discussionmentioning

confidence: 89%

Genipin increases oxaliplatin-induced cell death through autophagy in gastric cancer

Kim¹,

Jeong²,

Kim³

et al. 2020

J. Cancer

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Oxaliplatin is used for treatment in combination with many drugs. However, the survival rate is still low due to side effects and drug resistance. Therefore, the combination with natural products was required for increasing efficacy and reducing side effects. Genipin, a natural product derived from the Gardenia jasminoides, associated with anti-angiogenic, anti-proliferative, hypertension, inflammatory, and the Hedgehog pathway. It is not known that genipin increases the therapeutic effect of oxaliplatin in gastric cancer. In this study, we found that genipin sensitizes oxaliplatin-induced apoptosis for the first time using colony forming assay, FACS analysis, and western blotting in gastric cancer. Additionally, genipin induced p53 expression in AGS, MKN45, and MKN28 cells. Also, genipin induced autophagy and LC3 expression. Knockdown of LC3 decreased cell death enhanced by the combination of oxaliplatin and genipin. In summary, we showed that genipin increases the oxaliplatin-induced cell death via p53-DRAM autophagy. Based on this, we suggest that genipin is a sensitizer of oxaliplatin.

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Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer

Cited by 17 publications

References 50 publications

Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold

Genipin increases oxaliplatin-induced cell death through autophagy in gastric cancer

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