Study On The Killing Effect And Mechanism Of High Dose Vitamin C On Cholangiocarcinoma Cells

Part 1.Study on the killing effect and mechanism of high dose vitamin C on cholangiocarcinoma cellsCholangiocarcinoma(CC)is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy.Recent studies have revealed anti-cancer effect of vitamin C(L-ascorbic acid,ascorbate)in several types of cancer.However,the effect of L-ascorbic acid(AA)in CC remains elusive.Herein,we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species(ROS),and subsequently DNA damage,ATP depletion,m TOR pathway inhibition.Moreover,AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo.Intriguingly,sodium-dependent vitamin C transporter 2(SVCT-2)expression was inversely correlated with IC50 values of AA.Knockdown of SVCT-2 dramatically alleviated DNA damage,ATP depletion,and inhibition of m TOR pathway induced by AA.Furthermore,SVCT-2 knockdown endowed CC cells with the resistance to AA treatment.Finally,the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models.Thus,our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC.SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC.Part 2.Effect of high dose vitamin C on early recurrence of intrahepatic cholangiocarcinomaIntrahepatic cholangiocarcinoma(ICC)is a malignant tumor originating from intrahepatic bile duct epithelium,which is the second most common malignant tumor of liver except hepatocellular carcinoma.Surgical resection is still the only way to cure ICC,but early recurrence and high recurrence rate are the key factors of poor prognosis in patients with ICC.In addition to the high degree of malignancy,the lack of effective adjuvant therapy is also one of the factors that lead to poor prognosis.Recently,the anti-tumor effect of AA was reconfirmed in vivo and in vitro experiments and clinical trials. And our research group confirmed the effectiveness of high dose of AA on bile duct cancer with multiple basic research methods.In clinical practice,AA is a classical hepatoprotectants,which has been widely used in the recovery of liver function in acute and chronic hepatic injury.In our hospital,a part of the clinicians give patients with AA 2g/ day intravenously,who accepted partial hepatectomy surgery,lasting about 4-10 days.It has been reported that,given health adults 1.25 g AA intravenously,the blood concentration can reach 1200?M,which is enough to kill a variety of tumor cells in vitro.Therefore,we retrospectively reviewed the medical records of 370 ICC patients who underwent radical resection in our hospital.The results showed that high dose of AA had a good inhibitory effect on early recurrence after radical resection in patients with ICC.And the effect was more obvious in patients with Independent risk factors of early recurrence.So we suggest that high dose intravenous infusion of AA is expected to be a safe and effective adjunctive therapy for ICC patients.