Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells

Gong, Eun Yeung; Shin, Yong-June; Hwang, Ih Yeon; Kim, Jeong Hee; Kim, Seung Mi; Moon, Jung Hwan; Shin, Ji Sun; Lee, Dong Hoon; Hur, Dae Young; Jin, Dong Hoon; Hong, Seung Woo; Lee, Won Keun; Lee, Wang Jae

doi:10.1016/j.toxlet.2016.06.019

Cited by 25 publications

(14 citation statements)

References 36 publications

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“…Besides, it is important in cell apoptosis through various different pathways (24). Numerous studies have demonstrated that ROS is important for killing tumor cells in all types of living organisms (25,26). Besides, it may act as a second messenger to regulate cell proliferation, differentiation and apoptosis, which are associated with signal transduction pathways (10).…”

Section: Discussionmentioning

confidence: 99%

Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling

Peng

Song

et al. 2016

Oncology Letters

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Abstract. Icaritin has an advantage in enhancing immunity. Besides, with its anticancer effect, it may be of great help in cancer treatment and recovery of cancer patients. As a result, icaritin is likely to become a novel anticancer drug. However, the anticancer effect of icaritin against colon cancer has not been elucidated thus far. The present study investigated the latent anticancer effect of icaritin on the inhibition of colon cancer cell growth by regulating reactive oxygen species (ROS), B-cell lymphoma (Bcl)-2 and cyclin D1/E signaling. The COLO-205 colon cancer cell line was used as a colon cancer cell model in the present study. First, cell growth and apoptosis were measured to analyze the anticancer effect of icaritin against colon cancer. Next, the possible mechanism of icaritin against colon cancer, including ROS, Bcl-2, cyclin D1, cyclin E and caspase-3/9, was explored. The results revealed that icaritin could inhibit cell growth and induce the apoptosis of COLO-205 cells. In addition, icaritin significantly induced ROS generation, suppressed Bcl-2, cyclin D1 and cyclin E protein expression, and activated caspase-3/9 activity in COLO-205 cells. The present findings demonstrated that icaritin exerted antiproliferative and anticancer effects against colon cancer through the activation of ROS generation and the suppression of Bcl-2, cyclin D1 and cyclin E signaling.

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Section: Discussionmentioning

confidence: 99%

Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling

Peng

Song

et al. 2016

Oncology Letters

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“…Interestingly, the results of the present study showed that P-VC-Mg does not affect the generation of ROS by sorafenib. However, VC is known to produce ROS when given concomitantly with sulindac, 23) and lipid component of ascorbyl palmitate is reported to contribute to the generation of oxidized lipid metabolites that are epidermal cell toxicity. 24) Consequently, we expected VC to promote sorafenib-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

Yamamoto

Shichiri

Ishida³

et al. 2017

Biological & Pharmaceutical Bulletin

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Hand-foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.Key words vitamin C; multi-targeted tyrosine kinase inhibitor; hand-foot skin reaction (HFSR); ascorbic acidThe treatment for metastasis renal cell carcinoma has led to significant advances by molecular targeted drugs. However, some safety issues have recently emerged. In particular, adverse reactions induced by multiple tyrosine kinase inhibitors (mTKIs) are some of the major causes for the interruption of therapy involving these drugs. 1) Dermatological adverse events, also called hand−foot skin reaction, manifest topically in the palmar and plantar regions, and the pathological mechanism underlying these events is unclear. Because there are few treatment options for renal cell carcinoma and hepatocellular carcinoma, the success of therapy is determined by the length of efficient treatment and the management of adverse reactions. Therefore, appropriate management of the side effects will lead to an improvement in not only the QOL, but also the outcome of therapy 2,3) Although the dermatological adverse reactions induced by mTKIs are recognized as serious problems in clinical practice, a preventive method based on the pathological mechanism of these drugs has not been established.Previously, we reported that the inhibition of signal transducer and activator of transcription 3 (STAT3) contributes to the mechanism for keratinocyte toxicity induced by mTKIs, 4) and that the development of hand-foot skin reaction induced by mTKIs is associated with STAT3 polymorphisms. 5)STAT3 is a well-known transcriptional factor that regulates ce...

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“…Previous studies have established that ROS produced through the oxidation of AA is a crucial mediator of AA-induced cytotoxicity (Gong et al, 2016). Similarly, ROS production to induce oxidative stress is also the primary mechanism by which ATO causes apoptosis of tumor cells (Baysan et al, 2007).…”

Section: Ato/aa Combination Synergistically Produces Pro-apoptotic Efmentioning

confidence: 99%

Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis

et al. 2020

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Arsenic trioxide (ATO) is an effective therapeutic agent against acute promyelocytic leukemia (APL); however, its anti-tumor effect on solid tumors such as colorectal cancer (CRC) is still in debate. Ascorbic acid (AA) also produces a selective cytotoxic activity against tumor cells. Here, we exploit the potential benefit of ATO/AA combination in generating cytotoxicity to CRC cells, which may lay the groundwork for the potential combinational chemotherapy of CRCs. According to the results, we found that ATO and AA effectively inhibited the viability of human CRC cells in a synergistic manner. AA and ATO corporately activated caspase-3 to trigger apoptosis and upregulated the expression of caspase-1 and promoted formation of inflammasomes to induce pyroptosis. Furthermore, the stimulation of reactive oxygen species (ROS) overproduction was demonstrated as a subcellular mechanism for apoptosis and pyroptosis induced by ATO/AA combination treatment. Our findings suggest that ATO combination with a conventional dosage of AA offers an advantage for killing CRC cells. The synergistic action of ATO/AA combination might be considered a plausible strategy for the treatment of CRC and perhaps other solid tumors as well.

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Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells

Cited by 25 publications

References 36 publications

Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling

Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling

Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib

Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis

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