Open Access

Hexavalent chromium intoxication induces intrinsic and extrinsic apoptosis in human renal cells

  • Authors:
    • Yen‑Hung Wu
    • Jhong‑Ching Lin
    • Tzu‑Yi Wang
    • Tzeng‑Jih Lin
    • Meng‑Chi Yen
    • Yao‑Hua Liu
    • Pei‑Lin Wu
    • Fen‑Wei Chen
    • Yueh‑Lun Shih
    • I‑Jeng Yeh
  • View Affiliations

  • Published online on: December 16, 2019
  • Pages: 851-857
  • Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Hexavalent chromium [Cr(VI)], is a well‑known toxic form of the heavy metal chromium in the natural environment. Clinical evidence has indicated that exposure to Cr(VI) can cause severe renal damage. The production of reactive oxygen species (ROS) due to intracellular reduction of Cr(VI) is the main mechanism underlying the induction of cellular dysfunction and apoptosis. The present study aimed to investigate in detail the apoptotic pathways induced by Cr(VI)‑exposure in a human immortalized proximal tubular epithelial cell line HK‑2, in order to understand the mechanism involved therein. Exposure to 10 µM potassium dichromate (K2Cr2O7), a toxic compound of Cr(VI), significantly decreased cell viability after 24 and 48 h of incubation and induced intracellular ROS generation. The expression levels of markers that activate the apoptotic pathway including cleaved caspase‑3 and poly (ADP‑ribose) polymerase were significantly upregulated in K2Cr2O7‑exposed HK‑2 cells. In addition, the induction of intrinsic and extrinsic apoptotic markers was detected in K2Cr2O7‑exposed HK‑2 cells. In summary, the present study described for the first time the novel apoptotic mechanism of Cr(VI)‑toxicity in human renal cells which may be beneficial in designing optimal clinical treatment for renal damage caused by acute Cr(VI) toxicity.


Chromium is the sixth most abundant element in the earth's crust. Trivalent Cr(III) and hexavalent Cr(VI) chromium are the most stable oxidative states occurring in nature. Cr(VI) is more cytotoxic than Cr(III) due to its stronger oxidizing capacity and rapid absorption by the cells through non-specific anion carriers (1,2). Toxic Cr(VI) can be released into the environment through soil, sea water, and fresh water. As a result, individuals may be at a risk of exposure to Cr(VI) when consuming contaminated drinking water (3,4). The development of an optimal treatment scheme against acute or chronic Cr(VI) exposure remains a critical issue.

When Cr(VI) enters the cells, it can be rapidly reduced into Cr(III), resulting in the production of several reactive chromium intermediates and reactive oxygen species (ROS), all of which are responsible for altering normal cellular function and promoting apoptosis (5,6). Potassium dichromate (K2Cr2O7) is a toxic compound of Cr(VI) that has been demonstrated to induce nephrotoxicity in humans and animals (7). In a clinical setting, acute and chronic Cr(VI) exposure can cause severe damage to proximal renal tubular cells and result in significant renal function deterioration, thereby requiring hemodialysis (811). Cr(VI) toxicity causes acute tubular necrosis, whereby Cr(VI) directly damages the tubular epithelium (12). Less frequently, Cr(VI) also causes interstitial renal injury (13,14). Furthermore, Cr exposure can lead to hepatorenal syndrome, severe coagulopathy, and intravascular hemolysis that may indirectly contribute to the aggravation of renal dysfunction (13).

Cr(VI) induces free radical production by Fenton-type or Haber-Weiss reaction or by reacting directly with cellular molecules, triggering multiple possible apoptotic signaling pathways in various cell types (15,16). Several studies have suggested that Cr(VI) toxicity induced cell apoptosis mainly via intrinsic mitochondrial pathways in several types of cells, including human tumor cell lines, anterior pituitary cells, hepatocytic cells, and also in a rat model (5,1719). Although ROS is also linked to the extrinsic apoptotic pathway (20), it is not well understood whether the extrinsic apoptotic pathway is induced in renal cells post-Cr(VI) exposure. The aim of the present study was to investigate the activation of the extrinsic apoptotic pathway in Cr(VI)-exposed HK-2 human immortalized proximal tubular epithelial cell line HK-2.

Materials and methods

HK-2 cell culture

HK-2 cells (ATCC CRL-2190), an immortalized proximal tubular epithelial cell line derived from normal adult human kidneys, were purchased from the American Type Culture Collection. Culture conditions have been described in our previous study (21).

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay for cell viability

To determine the toxicity of chromium on kidney cells, HK-2 cells (1×104 cells) were seeded in each well of a 96-well culture plate (Falcon; BD Biosciences) in triplicates. The cells were exposed to potassium dichromate (K2Cr2O7; Sigma-Aldrich; Merck KGaA), which was used as the source of chromium (VI), at concentrations of 0.1, 0.3, 1, 10, 30, and 100 µM for 24, 48, and 72 h. Cell viability was directly examined by an Eclipse Ti-U inverted microscope (Nikon Corporation) at a magnification of ×400 and indirectly assayed by an MTT assay (Sigma-Aldrich; Merck KGaA) according to the manufacturer's instructions. The absorbance at 570 nm was determined using a microplate reader (Multiskan EX; LabSystems).

Oxidative stress assay

HK-2 cells (1×106) were incubated in 10-cm dishes with 5 µM 2′7′-dichlorofluorescein diacetate (Sigma-Aldrich; Merck KGaA) at 37°C for 30 min. After centrifugation (1,000 × g) and washing in phosphate-buffered saline, the HK-2 cells were exposed to 10 µM K2Cr2O7 each in triplicates. After 30 min of incubation, the fluorescence intensity, which is correlated to the concentration of hydroxyl radicals, was detected by Partec CyFlow (Sysmex Partec GmbH). The data were analyzed by FCS Express 4 Flow Cytometry (De Novo Software). All procedures were performed in the dark on ice.

Western blotting

Protein lysates were extracted using radioimmunoprecipitation lysis buffer (Amresco, LLC) containing 1% proteinase inhibitor on ice for 20 min. Proteins were quantified using the protein assay kit (based on Bradford method, Bio-Rad Laboratories, Inc.) and 30 µg protein per lane was loaded and separated by 10% sodium dodecyl sulfate-polyacrylamide electrophoresis at 100 V for 1 h. The separated proteins were transferred onto Hybond-P polyvinylidene difluoride membranes (Amersham Biosciences; GE Healthcare) and blocked with 3% bovine serum albumin in Tris-buffered saline containing Tween-20 for 1 h. The membranes were incubated overnight at 4°C with commercial primary monoclonal antibodies against poly (ADP-ribose) polymerase (PARP; catalogue number 9542S, 1:1,000; Cell Signaling Technology, Inc.), pro-caspase-3 (catalogue number 06–735, 1:1,000; EMD Millipore), cleaved caspase-3 (catalogue number C8487, 1:1,000; Sigma-Aldrich; Merck KGaA), Bcl-2 (catalogue number 658702, 1:1,000; BioLegend, Inc.), Bax (catalogue number 5023, 1:1,000; Cell Signaling Technology, Inc.), cytochrome c (catalogue number 05–479, 1:500; EMD Millipore), Fas ligand (FasL; catalogue number 68405, 1:500), apoptosis-inducing factor (AIF; catalogue number 4642, 1:1,000), pro-caspase-8 (catalogue number 9746S, 1:1,000) and cleaved caspase-8 (catalogue number 9496S, 1:1,000; all from Cell Signaling Technology, Inc.). Then, the membranes were incubated with goat anti-mouse IgG horseradish peroxidase (HRP)-conjugated antibodies (catalogue number 405306, 1:5,000) or anti-rabbit IgG HRP-conjugated antibodies (catalogue number 410406, 1:10,000; both from BioLegend, Inc.) at room temperature for 1 h. β-actin (catalog number MAB1501, 1:1,000; Chemicon; EMD Millipore) was used as an endogenous control and detected by the same secondary antibodies as aforementioned. Target proteins were visualized using Clarity™ Western ECL Substrate (Bio-Rad Laboratories, Inc.) and HyBlot CL film (Denville Scientific, Inc.). The intensities of the bands were quantified with ImageJ software 1.52a (NIH).

Statistical analysis

All results were expressed as the mean ± standard deviation (SD) of at least three independent experiments. Data were analyzed by analysis of variance (ANOVA) using SPSS20 software (IBM Corp.). Scheffe's test was used for post hoc analysis to compare all pairs of groups of the ANOVA test. Results were considered statistically significant at a value of P<0.05.


Cr(VI) exposure decreases cell viability and alters the morphology of HK-2 cells

To evaluate the toxic effect of Cr(VI) on renal tubular cells, a normal human proximal tubule epithelial cell line HK-2 was treated with different concentrations of K2Cr2O7, which produced Cr(VI) in aqueous solution. Various concentrations of K2Cr2O7 were added into culture medium and the cell viability was evaluated at 24 and 48 h post-K2Cr2O7 intoxication. The viability of 10-µM K2Cr2O7-treated cells was approximately 50–60 and 20–30%, at 24 and 48 h, respectively (Fig. 1A). To evaluate the toxic effect of K2Cr2O7 for 24–72 h, similar viability was obtained and is presented in Fig. 1B, compared to the control cells. The morphology of 10-µM K2Cr2O7-treated cells was altered. Significant cell shrinkage was observed when compared to the control cells (Fig. 1C). These results indicated that the morphology and viability of HK-2 cells were significantly affected upon exposure to 10 µM K2Cr2O7 for 24–72 h.

Cr(VI) exposure increases intracellular ROS production in HK-2 cells

Previous studies have suggested that the production of ROS during the reduction of Cr(VI) to Cr(III) promoted apoptosis (5,6). Thus, the intracellular level of ROS was assessed in HK-2 cells exposed to 10 and 100 µM of K2Cr2O7 for 30 min (Fig. 2A). The results revealed that the intracellular ROS level in 10 and 100 µM K2Cr2O7-exposed HK-2 cells was greater than that in control cells. Quantification of data also revealed similar results (Fig. 2B). A high level of ROS may be a factor that triggers cell death in K2Cr2O7-exposed HK-2 cells.

Cr(VI) exposure increases apoptosis in HK-2 cells

The results revealed that cells treated with 10 µM K2Cr2O7 for 48 h exhibited a viability of ~20–30%. Since a significant reduction in cell viability from 24 to 48 h suggested that apoptosis-regulating proteins were induced, the protein lysates were collected during a 24 to 48-h time frame. The protein lysates of HK-2 cells exposed to K2Cr2O7 were harvested at 24, 36, 40, and 45 h (Fig. 3A) and the quantitative results are presented in Fig. 3B-E. The activation of caspase-3 and cleavage of PARP indicated activation of the apoptotic pathway (22). After 24 h of K2Cr2O7 exposure, the expression levels of cleaved PARP and cleaved caspase-3 were significantly upregulated. In addition, the expression of Bcl-2, which prevents the release of mitochondrial apoptogenic factors such as cytochrome c and AIF (23), was significantly suppressed in K2Cr2O7-exposed HK-2 cells, indicating that 10 µM K2Cr2O7 exposure induced apoptotic pathways at 24 h post-K2Cr2O7 treatment. At other time-points, similar expression patterns were observed. However, there was no significant difference between the control and 10-µM K2Cr2O7-exposed cells at 36, 40 and 45 h due to high standard deviation.

Cr(VI) exposure increases not only the intrinsic, but also the extrinsic and caspase-independent apoptosis in HK-2 cells

Previous studies have revealed that Cr(VI) toxicity induced cell apoptosis mainly via intrinsic mitochondrial pathways (5). Our results showed that the expression levels of molecules involved in the intrinsic pathway (BAX, cytochrome c), caspase-independent pathway (AIF), and extrinsic pathway (soluble FasL and cleaved caspase-8) were significantly induced after 45 h of incubation in the presence of 10 µM K2Cr2O7 (Fig. 4). These findings indicated that these pathways contributed to Cr(VI)-mediated human renal cell death. The summary of this study is outlined in Fig. 5.


Exposure to Cr(VI) affects various physiological events, and Cr(VI)-induced apoptosis has been reported by previous studies. In human diploid and normal fibroblasts and in HeLa human cervical cancer cells, reduced form of Cr(VI) caused DNA strand breaks (2426). In U937 cells, exposure to 20 µM Cr(VI) for 24 h induced intrinsic but not extrinsic apoptosis (27). Exposure to 30 µM Cr(VI) induced both p53-dependent and independent intrinsic mitochondrial apoptosis in HCT116 human colon carcinoma cells (28). Activation of ribosomal protein L3 (rpL3) plays a role in chemotherapeutic drug-induced p53-independent apoptosis in colon and lung cancer cells (29,30). However, the role of rpL3 in Cr(VI)-induced apoptotic processes is unclear. Another study revealed that Bcl-2 and p21 were downregulated after HCT-116 cells were exposed to 30 µM Cr(VI) (5). In a rat model, a single subcutaneous injection of K2Cr2O7 at 15 mg/kg induced the intrinsic mitochondrial pathway in kidneys (19). Clinically, Cr(VI) exposure often causes acute renal failure that may result in permanent hemodialysis or even death, and renal injury has mainly been detected in renal proximal tubular epithelial cells (31). Therefore, investigating the mechanism of Cr(VI)-induced apoptosis in renal cells is an important issue. To develop an optimal strategy to treat acute Cr(VI) intoxication, the apoptosis mechanism in human kidney cells under a curable dose was evaluated. According to a clinical study, chromium at a concentration of 10 mg/l (approximate 34 µM) or greater in human blood is considered to be lethal for human life (32). A case study indicated that a patient with chromium blood concentration of 3.4 mg/l fortunately survived after intermittent hemodialysis treatment (33). Compared to cells exposed to 10 µM of Cr(VI), low cell viability was observed when cells were exposed to 30 and 100 µM for 24 and 48 h (Fig. 1A). Conversely, cell viability was relatively high when cells were exposed to low concentrations of Cr (VI) (<10 µM). Therefore, the present results also indicated that higher concentrations were lethal and lower doses may not induce apoptosis. Cr(VI) toxicity at 10 µM (2.95 mg/l) was selected to induce apoptosis in the HK-2 human proximal tubular epithelial cell line.

The intrinsic pathway is regulated by pro-apoptotic and anti-apoptotic proteins such as Bax and Bcl-xL, respectively (22). These proteins alter the fate of cytochrome c release and activation of the caspase cascade, which regulate the permeability of the outer mitochondrial membrane (22). Increased Bax and decreased Bcl-2 protein expression indicated that the intrinsic mitochondrial apoptotic pathway was induced in HK-2 cells (Figs. 3 and 4). AIF is a pro-apoptotic protein released from the mitochondria, and its nuclear translocation caused DNA fragmentation and was involved in caspase-independent apoptosis (34,35). Extrinsic apoptotic pathways initiate apoptosis via the interaction between ligands and transmembrane receptors that belong to the tumor necrosis factor (TNF) receptor gene superfamily (22). Induction of extrinsic apoptosis was observed in mouse glomerular podocytes when they were exposed to toxic metals such as arsenite, cadmium, and mercury (36). Increased expression of soluble FasL and cleaved caspase-8 was detected after 10 µM Cr(VI) toxicity. Soluble FasL is well known as a degradation product of the membrane form of FasL by matrix metalloproteinases (37,38). Previous studies have documented that chromium had the potential to enhance the function of matrix metalloproteinases (39,40), which may explain the increased ratio between soluble and membrane FasL in the present results. In addition, the prevalence of the soluble form in association with the increased activation of caspase-8 (cleaved caspase-8) indicated the possible active role of soluble FasL in chromium-induced HK-2 cell apoptosis. Therefore, the present results indicated that Cr(VI) toxicity for 48 h triggered the extrinsic apoptotic pathway. To the best of our knowledge, this study is the first to observe the induction of extrinsic apoptotic markers in Cr(VI)-exposed human renal cells. However, the mechanism of Cr(VI)-induced soluble FasL release is still unknown. The crosstalk between tumor necrosis factors and ROS may be a potential explanation (41), but further studies are required to confirm this hypothesis.

The limitation of the present study is that the conclusions were supported by one technique in one cell line. For confirmation, more experiments are required in future studies. For example, cell death can be also detected via BrdU staining assay and Annexin V staining assay at each time-point. Inhibition of intrinsic and extrinsic apoptosis-dependent pathways via specific inhibitors on caspase-8 and caspase-9 may further confirm the most critical pathways at specific time-points. To further investigate the role of Cr(VI)-induced ROS production, treatments with antioxidants or ROS scavengers are strategies for future experiments. In addition, performing animal experiments may strengthen our conclusion.

Collectively, not only intrinsic but also extrinsic apoptotic pathway-related apoptotic markers were activated in an immortalized proximal tubular epithelial cell line after exposure to 10 µM activated Cr(VI). The experimental dosage of Cr(VI) was similar to the Cr(VI) dosage that causes acute renal dysfunction. It is anticipated that the present study may be beneficial in designing optimal treatments for acute Cr(VI) toxicity in the future.


The authors would like to thank Professor Jung-San Chang (Department of Renal Care, College of Medicine, Kaohsiung Medical University) for scientific discussions and technical assistance.


The present study was supported by grants from the Kaohsiung Medical University Hospital (grant no. KMUH103-3M52).

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Authors' contributions

YHW, JCL and IJY designed the study. PLW and FWC performed the experiments. YHW, TYW, TJL, MCY, YLS, YHL, and IJY analyzed the data and interpreted the results. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





hexavalent chromium


reactive oxygen species


trivalent chromium


poly (ADP-ribose) polymerase


apoptosis-inducing factor



Wang XF, Xing ML, Shen Y, Zhu X and Xu LH: Oral administration of Cr(VI) induced oxidative stress, DNA damage and apoptotic cell death in mice. Toxicology. 228:16–23. 2006. View Article : Google Scholar : PubMed/NCBI


Sun H, Brocato J and Costa M: Oral chromium exposure and toxicity. Curr Environ Health Rep. 2:295–303. 2015. View Article : Google Scholar : PubMed/NCBI


Izbicki JA, Wright MT, Seymour WA, BlaineMcCleskey R, Fram MS, Belitz KF and Esser BK: Cr(VI) occurrence and geochemistry in water from public-supply wells in California. Appl Geochem. 63:203–217. 2015. View Article : Google Scholar


Chen Y, An D, Sun S, Gao J and Qian L: Reduction and removal of chromium VI in water by powdered activated carbon. Materials (Basel). 11(pii): E2692018. View Article : Google Scholar : PubMed/NCBI


Chiu A, Shi XL, Lee WK, Hill R, Wakeman TP, Katz A, Xu B, Dalal NS, Robertson JD, Chen C, et al: Review of chromium (VI) apoptosis, cell-cycle-arrest, and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 28:188–230. 2010. View Article : Google Scholar : PubMed/NCBI


Hu G, Zheng P, Feng H and Jia G: Imbalance of oxidative and reductive species involved in chromium(VI)-induced toxic effects. Reactive Oxygen Species. 3:12017.


Liu KJ and Shi X: In vivo reduction of chromium (VI) and its related free radical generation. Mol Cell Biochem. 222:41–47. 2001. View Article : Google Scholar : PubMed/NCBI


Pan TL, Wang PW, Chen CC, Fang JY and Sintupisut N: Functional proteomics reveals hepatotoxicity and the molecular mechanisms of different forms of chromium delivered by skin administration. Proteomics. 12:477–489. 2012. View Article : Google Scholar : PubMed/NCBI


Bright P, Burge PS, O'Hickey SP, Gannon PF, Robertson AS and Boran A: Occupational asthma due to chrome and nickel electroplating. Thorax. 52:28–32. 1997. View Article : Google Scholar : PubMed/NCBI


Costa M: Toxicity and carcinogenicity of Cr(VI) in animal models and humans. Crit Rev Toxicol. 27:431–442. 1997. View Article : Google Scholar : PubMed/NCBI


Verschoor MA, Bragt PC, Herber RF, Zielhuis RL and Zwennis WC: Renal function of chrome-plating workers and welders. Int Arch Occup Environ Health. 60:67–70. 1988. View Article : Google Scholar : PubMed/NCBI


Wedeen RP and Qian LF: Chromium-induced kidney disease. Environ Health Perspect. 92:71–74. 1991. View Article : Google Scholar : PubMed/NCBI


Sharma BK, Singhal PC and Chugh KS: Intravascular haemolysis and acute renal failure following potassium dichromate poisoning. Postgrad Med J. 54:414–415. 1978. View Article : Google Scholar : PubMed/NCBI


Ellis EN, Brouhard BH, Lynch RE, Dawson EB, Tisdell R, Nichols MM and Ramirez F: Effects of hemodialysis and dimercaprol in acute dichromate poisoning. J Toxicol Clin Toxicol. 19:249–258. 1982. View Article : Google Scholar : PubMed/NCBI


Leonard SS, Roberts JR, Antonini JM, Castranova V and Shi X: PbCrO4 mediates cellular responses via reactive oxygen species. Mol Cell Biochem. 255:171–179. 2004. View Article : Google Scholar : PubMed/NCBI


Sinha K, Das J, Pal PB and Sil PC: Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 87:1157–1180. 2013. View Article : Google Scholar : PubMed/NCBI


Quinteros FA, Poliandri AH, Machiavelli LI, Cabilla JP and Duvilanski BH: In vivo and in vitro effects of chromium VI on anterior pituitary hormone release and cell viability. Toxicol Appl Pharmacol. 218:79–87. 2007. View Article : Google Scholar : PubMed/NCBI


Xiao F, Li Y, Dai L, Deng Y, Zou Y, Li P, Yang Y and Zhong C: Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes. Int J Mol Med. 30:629–635. 2012. View Article : Google Scholar : PubMed/NCBI


Molina-Jijon E, Tapia E, Zazueta C, El Hafidi M, Zatarain-Barrón ZL, Hernández-Pando R, Medina-Campos ON, Zarco-Márquez G, Torres I and Pedraza-Chaverri J: Curcumin prevents Cr(VI)-induced renal oxidant damage by a mitochondrial pathway. Free Radic Biol Med. 51:1543–1557. 2011. View Article : Google Scholar : PubMed/NCBI


Redza-Dutordoir M and Averill-Bates DA: Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta. 1863:2977–2992. 2016. View Article : Google Scholar : PubMed/NCBI


Lin TJ, Huang YL, Chang JS, Liu KT, Yen MC, Chen FW, Shih YL, Jao JC, Huang PC and Yeh IJ: Optimal dosage and early intervention of L-ascorbic acid inhibiting K2Cr2O7-induced renal tubular cell damage. J Trace Elem Med Biol. 48:1–7. 2018. View Article : Google Scholar : PubMed/NCBI


Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI


Tsujimoto Y: Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells. 3:697–707. 1998. View Article : Google Scholar : PubMed/NCBI


Snyder RD: Role of active oxygen species in metal-induced DNA strand breakage in human diploid fibroblasts. Mutat Res. 193:237–246. 1988.PubMed/NCBI


Wakeman TP, Kim WJ, Callens S, Chiu A, Brown KD and Xu B: The ATM-SMC1 pathway is essential for activation of the chromium[VI]-induced S-phase checkpoint. Mutat Res. 554:241–251. 2004. View Article : Google Scholar : PubMed/NCBI


Ha L, Ceryak S and Patierno SR: Generation of S phase-dependent DNA double-strand breaks by Cr(VI) exposure: Involvement of ATM in Cr(VI) induction of gamma-H2AX. Carcinogenesis. 25:2265–2274. 2004. View Article : Google Scholar : PubMed/NCBI


Hayashi Y, Kondo T, Zhao QL, Ogawa R, Cui ZG, Feril LB Jr, Teranishi H and Kasuya M: Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells. Toxicol Appl Pharmacol. 197:96–106. 2004. View Article : Google Scholar : PubMed/NCBI


Hill R, Leidal AM, Madureira PA, Gillis LD, Cochrane HK, Waisman DM, Chiu A and Lee PW: Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/-HCT116 colon cancer cells. DNA Repair (Amst). 7:239–252. 2008. View Article : Google Scholar : PubMed/NCBI


Pagliara V, Saide A, Mitidieri E, d'Emmanuele di Villa Bianca R, Sorrentino R, Russo G and Russo A: 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-beta-synthase in colon cancer cells lacking p53. Oncotarget. 7:50333–50348. 2016. View Article : Google Scholar : PubMed/NCBI


Russo A, Saide A, Cagliani R, Cantile M, Botti G and Russo G: rpL3 promotes the apoptosis of p53 mutated lung cancer cells by down-regulating CBS and NFκB upon 5-FU treatment. Sci Rep. 6:383692016. View Article : Google Scholar : PubMed/NCBI


Parveen K, Khan MR and Siddiqui WA: Pycnogenol prevents potassium dichromate K2Cr2O7-induced oxidative damage and nephrotoxicity in rats. Chem Biol Interact. 181:343–350. 2009. View Article : Google Scholar : PubMed/NCBI


Pedersen RS and Morch PT: Chromic acid poisoning treated with acute hemodialysis. Nephron. 22:592–595. 1978. View Article : Google Scholar : PubMed/NCBI


KhanSaif R, Aparna Q, Shahzad S and Haque F: Chromium induced AKI: Case with protean implications. Annals Tropical Medicine Public Health. 7:136–138. 2014.


Tait SW and Green DR: Caspase-independent cell death: Leaving the set without the final cut. Oncogene. 27:6452–6461. 2008. View Article : Google Scholar : PubMed/NCBI


Ranjan A and Iwakuma T: Non-canonical cell death induced by p53. Int J Mol Sci. 17(pii): E20682016. View Article : Google Scholar : PubMed/NCBI


Eichler T, Ma Q, Kelly C, Mishra J, Parikh S, Ransom RF, Devarajan P and Smoyer WE: Single and combination toxic metal exposures induce apoptosis in cultured murine podocytes exclusively via the extrinsic caspase 8 pathway. Toxicol Sci. 90:392–399. 2006. View Article : Google Scholar : PubMed/NCBI


Vargo-Gogola T, Crawford HC, Fingleton B and Matrisian LM: Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys. 408:155–161. 2002. View Article : Google Scholar : PubMed/NCBI


Musial K and Zwolinska D: Matrix metalloproteinases and soluble Fas/FasL system as novel regulators of apoptosis in children and young adults on chronic dialysis. Apoptosis. 16:653–659. 2011. View Article : Google Scholar : PubMed/NCBI


Cammarota M, Lamberti M, Masella L, Galletti P, De Rosa M, Sannolo N and Giuliano M: Matrix metalloproteinases and their inhibitors as biomarkers for metal toxicity in vitro. Toxicol In Vitro. 20:1125–1132. 2006. View Article : Google Scholar : PubMed/NCBI


Wan R, Mo Y, Zhang X, Chien S, Tollerud DJ and Zhang Q: Matrix metalloproteinase-2 and −9 are induced differently by metal nanoparticles in human monocytes: The role of oxidative stress and protein tyrosine kinase activation. Toxicol Appl Pharmacol. 233:276–285. 2008. View Article : Google Scholar : PubMed/NCBI


Blaser H, Dostert C, Mak TW and Brenner D: TNF and ROS crosstalk in inflammation. Trends Cell Biol. 26:249–261. 2016. View Article : Google Scholar : PubMed/NCBI

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Wu, Y., Lin, J., Wang, T., Lin, T., Yen, M., Liu, Y. ... Yeh, I. (2020). Hexavalent chromium intoxication induces intrinsic and extrinsic apoptosis in human renal cells. Molecular Medicine Reports, 21, 851-857.
Wu, Y., Lin, J., Wang, T., Lin, T., Yen, M., Liu, Y., Wu, P., Chen, F., Shih, Y., Yeh, I."Hexavalent chromium intoxication induces intrinsic and extrinsic apoptosis in human renal cells". Molecular Medicine Reports 21.2 (2020): 851-857.
Wu, Y., Lin, J., Wang, T., Lin, T., Yen, M., Liu, Y., Wu, P., Chen, F., Shih, Y., Yeh, I."Hexavalent chromium intoxication induces intrinsic and extrinsic apoptosis in human renal cells". Molecular Medicine Reports 21, no. 2 (2020): 851-857.