Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

Liang, Wenquan; Cai, Aizhen; Chen, Guozhu; Xi, Hongqing; Wu, Xiaosong; Cui, Jianxin; Zhang, Kecheng; Zhao, Xudong; Yu, Jiyun; Wei, Bo; Chen, Lin

doi:10.1038/srep38267

Cited by 73 publications

(56 citation statements)

References 50 publications

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“…In cancer cells, ROS are upregulated compared to normal cells [33]. However, contrary to tumor-promoting effects, cancer is more sensitive to ROS-induced apoptosis once ROS exceed certain physiological thresholds [17,29]. Therefore, increasing the intracellular ROS concentration is an effective anticancer strategy [20].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, increasing the intracellular ROS concentration is an effective anticancer strategy [20]. Previous reports have indicated that OXA-induced apoptosis is mediated by increased intracellular levels of ROS and the consequent mitochondrial apoptosis [3,[17][18][19]. In addition, H 2 S was highly associated with ROS resistance and AOAA upregulated ROS and P53 by inhibiting H 2 S synthesis [7,12,16].…”

Section: Discussionmentioning

confidence: 99%

“…However, the effect of inhibition of the CBS/H 2 S axis on the sensitivity of colon cancer cells to OXA has not been illustrated. Increased production of ROS and P53 has been implicated in the apoptosis of colon cancer cells induced by OXA [3,[17][18][19][20][21]. One of the mechanisms underlying the acquired resistance of OXA is increased intracellular GSH and consequently increased detoxification of ROS [22].…”

Section: Introductionmentioning

confidence: 99%

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Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS

Yue¹,

Zuo²,

Bu³

et al. 2020

J. Cancer

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Background: As the third confirmed gaseous transmitter, the role of hydrogen sulfide (H2S) in the pathogenesis of multiple types of cancer has been attracting increasing attention. Increased expression of cystathionine β-synthase (CBS) and H2S in colon cancer tissue samples has been validated and tumor-derived H2S, mainly produced by CBS, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Recently, the therapeutic manipulation of H2S has been proposed as a promising anticancer approach. However, the effect of aminooxyacetic acid (AOAA), which has been widely used as an inhibitor of CBS dependent synthesis of H2S, on the chemotherapeutic effect of oxaliplatin (OXA) and the underlying mechanisms remain to be illustrated. Methods: We examined the expression of CBS in human colorectal cancer specimens and matched normal mucosa by immunohistochemistry. The effect of AOAA on the sensitivity of colon cancer cells to OXA and the level of apoptosis induced by caspase cascade was investigated in both HCT116 and HT29 cell lines utilizing CCK-8 assays, flow cytometry analysis and western blot analysis. The endogenous levels of reactive oxygen species (ROS) were detected fluorescently by DCF-DA, and glutathione (GSH) levels were measured by a Total GSH Detection Kit. Tumor bearing xenograft mouse models and in vivo imaging systems were further used to investigate the effect of AOAA in vivo and immunohistochemistry (IHC) and TUNEL analysis were performed. Results: In the current study, we confirmed CBS, the main target of AOAA, is overexpressed in human colorectal cancer by immunohistochemistry. The inhibitory effect of AOAA on the synthesis of H2S was validated utilizing fluorescent probe and specific electrode. AOAA significantly reduced the IC50 values of OXA in both colon cancer cell lines. Co-incubation with AOAA elicited increased apoptosis induced by OXA, featured by increased activation of caspase cascade. Besides, AOAA further increased the levels of ROS induced by OXA and attenuated the synthesis of glutathione (GSH), which is a vital antioxidant. Besides, the results of in vivo imaging and following IHC and TUNEL analysis were in accordance with cellular experiments, indicating that AOAA sensitizes colon cancer cells to OXA via exaggerating intrinsic apoptosis. Conclusion: The results suggested that CBS is overexpressed in colorectal cancer tissues and AOAA sensitizes colon cancer cells to OXA via exaggerating apoptosis both in vitro and in vivo. Decreasing the endogenous level of GSH and consequently impaired detoxification of ROS might be one of the mechanisms underlying the effect of AOAA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS

Yue¹,

Zuo²,

Bu³

et al. 2020

J. Cancer

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“…Furthermore, shikonin suppresses tumor growth in xenograft animal models and increases lipid peroxidation and apoptosis in vivo. Finally, shikonin enhances the antitumor activities of 5-fluorouracil and oxaliplatin in vivo [87]. Another natural compound of some fruits and vegetables with antitumoral properties in lung cancer, leukemia, and breast cancer is quercetin.…”

Section: Natural Compoundsmentioning

confidence: 99%

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

et al. 2020

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Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s.

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“…Shikonin is able to inhibit cell proliferation and induces apoptosis in several human malignancies such as gastric cancer [3], non-small cell lung cancer [4], pancreatic cancer [5] and so on. However, certain limitations exist, including no clear target and liver and kidney toxicity [6].…”

Section: Introductionmentioning

confidence: 99%

Acetylshikonin Inhibits Colorectal Cancer Growth via PI3K/Akt/mTOR Signaling Pathway

Zhu¹,

Zhong²,

Zhou³

et al. 2018

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Background: Acetylshikonin, a major constituent isolated from Arnebia euchroma, is a potential candidate for anti-colorectal cancer drugs. However, the potential activity and underlying mechanism of Acetylshikonin against colorectal cancer remain unclear. Methods: In this study, Acetylshikonin was isolated from the active CHCl3 extract of Arnebia euchroma using activity-guided screening, and elucidated by the extensive spectroscopic analysis and comparison with literature data. Human colorectal cancer cells HT29, DLD-1, HCT116 or Caco-2 were exposed to different concentrations of Acetylshikonin (6.25 -100 μg/mL) for 24 or 48 h. Cell viability, cell apoptosis and cell cycle distribution were detected. The activity of Acetylshikonin and potential mechanism of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were evaluated in vitro and vivo. Results: We found that Acetylshikonin exhibited remarkable anti-proliferative activity in a dose-dependent manner against HT29 cells with the IC50 values of 60.82 μg/ml and 30.78 μg/ml at 24, 48 h, respectively. Moreover, Acetylshikonin induced cell cycle arrest at G0/G1 phase and early apoptosis through inhibition of PI3K/Akt/mTOR pathway. Furthermore, the assays of cell inhibition, early

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Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

Cited by 73 publications

References 50 publications

Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS

Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

Acetylshikonin Inhibits Colorectal Cancer Growth via PI3K/Akt/mTOR Signaling Pathway

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