Prognostic implications of immune classification using IDO1 expression in extrahepatic bile duct carcinoma.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme that catalyzes the degradation of tryptophan to kynurenine and induces immune tolerance in tumor cells. The effects of IDO1 on extrahepatic bile duct carcinoma (EHBDC) are poorly understood. Therefore, the present study aimed to investigate the expression and prognostic significance of IDO1 in EHBDC. An immunohistochemical microarray analysis of IDO1 expression was performed for 76 surgically resected cases of EHBDC. CD8+ tumor infiltrating lymphocytes (TILs) were also investigated through a combination analysis with IDO1 expression. IDO1 was highly expressed in 25 of 76 (32.9%) cases. High expression of IDO1 was associated with decreased numbers of CD8+ TILs (P=0.008), a higher pN category (P=0.007), an advanced overall stage (P=0.001) and frequent recurrence (P=0.018). When IDO1 expression was further stratified with CD8+ TIL state, the IDO1high/CD8low subgroup was decreased in terms of overall survival (P=0.025) and disease-free survival (P=0.015) compared with IDO1high/CD8high, IDO1low/CD8high and IDO1low/CD8low subgroups. High IDO1 expression was associated with a decreased number of CD8+ TILs and associated with a poor prognosis. As IDO1 may be a new target of immunotherapy applications, IDO1/CD8+ TIL subgrouping can be a useful prognostic and predictive tool in patients with EHBDC.

Novel Biomarker Panels Discriminating between Pancreatic Ductal Adenocarcinoma and Extrahepatic Bile Duct Carcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic bile duct carcinoma (EBDC) are distinct entities with different clinicopathological implications. Therefore, research to differentiate between the two diseases is compulsory. In this study, four biomarkers were selected (Hippocalcin-like 1 (HPCAL1); annexin A10 (ANXA10); MUC5AC; sodium/potassium-transporting ATPase subunit beta-1 (ATP1B1)) and focus was placed on clarifying the diagnostic performance of each biomarker and pioneering novel-combined biomarker panels to discriminate between PDAC and EBDC. PROCEDURES: An immunohistochemical microarray analysis of HPCAL1, ANXA10, MUC5AC, and ATP1B1 was conducted for surgically resected 55 PDACs and 77 EBDCs. The diagnostic performance discriminating between PDAC and EBDC was evaluated using four biomarkers and the combined biomarker panels. RESULTS: PDACs exhibited more positive expressions for HPCAL1, ANXA10, and MUC5AC, whereas EBDCs exhibited more ATP1B1-positive expressions. The PDAC panel with the best diagnostic performance was the profile of (+ in ≥ 2 among HPCAL1, ANXA10, MUC5AC)/ATP1B1-. The immunophenotype pattern of (- in ≥ 1 among HPCAL1, ANXA10, MUC5AC)/ATP1B1+ is the EBDC panel with the most excellent discriminating power. CONCLUSION: The suggested combined biomarker panels demonstrate the distinguishing diagnostic ability between PDAC and EBDC is better than previous studies. Therefore, for differentiation between PDAC and EBDC, these panels are expected to help unravel the clinicopathological enigma as promising biomarker panels in the future.

Can heme oxygenase-1 be a prognostic factor in patients with hepatocellular carcinoma?

Heme oxygenase-1 (HO-1) is an important catalytic enzyme in heme degradation, which increases during stressful conditions. It plays a major role in antioxidative and antiapoptotic processes and is associated with tumor growth and metastasis.This study aimed to evaluate the degree of HO-1 expressions in hepatocellular carcinoma (HCC) surgical specimens and the correlation between HO-1 expression and patient prognosis. Formalin-fixed, paraffin-embedded HCC tissue samples (n = 96) were included in the analysis, and the expression of HO-1 was evaluated by immunohistochemical staining. We reviewed clinical features of patients and evaluated the prognostic role of HO-1 in patient survival and recurrence.Positive HO-1 expression was identified in 43 cases (44.8%) and was frequently found in patients with advanced histology (Edmondson-Steiner [E-S] grade 2, 3, 4), α-fetoprotein (AFP) level of more than 200 IU/mL, and the presence of microvascular and capsular invasion (P < .05). In the univariate analysis, the overall survival (OS) and disease-free survival (DFS) of patients with HO-1-positive HCC were not statistically different from those with HO-1-negative HCC. Moreover, HO-1 expression was not associated with patient survival and recurrence based on the multivariate analysis. In the subgroup analysis of patients without preoperative transarterial chemoembolization (TACE) (n = 61), HO-1 was not also associated with tumor recurrence (P = .681).The clinical implication of HO-1 activity is controversial in various malignancies. However, HO-1 expression did not seem to influence the prognosis of HCC patients.

PPARß/δ agonist GW501516 inhibits TNFα-induced repression of adiponectin and insulin receptor in 3T3-L1 adipocytes.

Previous reports have shown that PPARß/δ agonists ameliorate insulin resistance associated with type 2 diabetes mellitus (T2DM). To determine the role of PPARß/δ in tumor necrosis factor α (TNFα)-mediated insulin resistance, we investigated expression levels of adiponectin and insulin receptor (IR) in response to treatment with the PPARß/δ agonist GW501516 with or without TNFα, a proinflammatory cytokine, in differentiated 3T3-L1 adipocytes. GW501516 induced adipocyte differentiation and the expression of adiponectin in a dose-dependent manner in differentiated adipocytes. TNFα treatment reduced adiponectin expression at the end of differentiation. This effect was reversed by GW501516 co-treatment with TNFα. TNFα treatment decreased adipogenic marker genes such as PPARγ, aP2, resistin, and GLUT4, and GW501516 reversed the effects of TNFα. GW501516 treatment increased the expression of insulin receptor and inhibited TNFα-mediated repression of insulin receptor. Our results showed that GW501516 abrogated TNFα-induced insulin resistance. In summary, our study demonstrated that the PPARß/δ agonist, GW501516 reversed TNFα-induced decreases in adipocyte differentiation and adiponectin expression, and improved insulin sensitivity by increasing the expression of insulin receptor. Therefore, PPARδ may be a promising therapeutic target for treatment of insulin resistance in patients with T2DM.

Protective Effect of Artemisia argyi and Its Flavonoid Constituents against Contrast-Induced Cytotoxicity by Iodixanol in LLC-PK1 Cells.

Preventive effects and corresponding molecular mechanisms of mugwort (Artemisia argyi) extract and its flavonoid constituents on contrast-induced nephrotoxicity were explored in the present study. We treated cultured LLC-PK1 cells with iodixanol to induce contrast-induced nephrotoxicity, and found that A. argyi extracts ameliorated the reduction in cellular viability following iodixanol treatment. The anti-apoptotic effect of A. argyi extracts on contrast-induced nephrotoxicity was mediated by the inhibition of mitogen-activated protein kinase (MAPK) phosphorylation and the activation of caspases. The flavonoid compounds isolated from A. argyi improved the viability of iodixanol-treated cells against contrast-induced nephrotoxicity. Seven compounds (1, 2, 3, 15, 16, 18, and 19) from 19 flavonoids exerted a significant protective effect. Based on the in silico oral-bioavailability and drug-likeness assessment, which evaluate the drug potential of these compounds, compound 2 (artemetin) showed the highest oral bioavailability (49.55%) and drug-likeness (0.48) values. We further investigated the compound⁻target⁻disease network of compound 2, and proliferator-activated receptor gamma (PPAR-γ) emerged as a predicted key marker for the treatment of contrast-induced nephrotoxicity. Consequently, compound 2 was the preferred candidate, and its protective effect was mediated by inhibiting the contrast-induced inflammatory response through activation of PPAR-γ and inhibition of MAPK phosphorylation and activation of caspases.

Corrigendum to: Effects of salmon DNA fraction in vitro and in a monosodium iodoacetate-induced osteoarthritis rat model.

[This corrects the article on p. 163 in vol. 22, PMID: 29520169.].

Effects of salmon DNA fraction in vitro and in a monosodium iodoacetate-induced osteoarthritis rat model.

PRF001 is a fragmented DNA polymer extracted from the testes of salmon. The purpose of this study was to assess the anti-inflammatory effect of PRF001 in vitro as well as the protective effect of PRF001 intake against arthritis in a rat model. In vitro, cell survival and inflammatory markers after H2O2 treatment to induce cell damage were investigated in CHON-001 cells treated with different concentrations of PRF001. In vivo, osteoarthritis was induced by intra-articular injection of monosodium iodoacetate (MIA) into the knee joints of rats. After consumption of PRF001 (10, 50, or 100 mg/kg) for 4 weeks, inflammatory mediators and cytokines in articular cartilage were investigated. In vitro, the levels of inflammatory markers, IL-1ß, TNF-α, COX-2, iNOS, and PGE2, were significantly suppressed by PRF001 treatment. In vivo, the inflammatory mediators and cytokines, IL-1ß, p-Erk1/2, NF-κB, TNF-α, COX-2, and PGE2, as well as MMP3 and MMP7, which have catabolic activity in chondrocytes, were decreased in the MIA-induced osteoarthritic rats following intake of PRF001. Histological analysis revealed that PRF001 had a protective effect on the articular cartilage. Altogether, these results demonstrated that the anti-inflammatory property of PRF001 contributes to its protective effects in osteoarthritis through deregulating IL-1ß, TNF-α, and subsequent signals, such as p-Erk1/2, NF-κB, COX-2, PGE2, and MMPs.

Beneficial effects of fermented black ginseng and its ginsenoside 20(S)-Rg3 against cisplatin-induced nephrotoxicity in LLC-PK1 cells.

BACKGROUND: Nephrotoxicity is a common side effect of medications. Panax ginseng is one of the best-known herbal medicines, and its individual constituents enhance renal function. Identification of its efficacy and mechanisms of action against drug-induced nephrotoxicity, as well as the specific constituents mediating this effect, have recently emerged as an interesting research area focusing on the kidney protective efficacy of P. ginseng. METHODS: The present study investigated the kidney protective effect of fermented black ginseng (FBG) and its active component ginsenoside 20(S)-Rg3 against cisplatin (chemotherapy drug)-induced damage in pig kidney (LLC-PK1) cells. It focused on assessing the role of mitogen-activated protein kinases as important mechanistic elements in kidney protection. RESULTS: The reduced cell viability induced by cisplatin was significantly recovered with FBG extract and ginsenoside 20(S)-Rg3 dose-dependently. The cisplatin-induced elevated protein levels of phosphorylated c-Jun N-terminal kinase (JNK), p53, and cleaved caspase-3 were decreased after cotreatment with FBG extract or ginsenoside 20(S)-Rg3. The elevated percentage of apoptotic LLC-PK1 cells induced by cisplatin treatment was significantly abrogated by cotreatment with FBG and the ginsenoside 20(S)-Rg3. CONCLUSION: FBG and its major ginsenoside 20(S)-Rg3, ameliorated cisplatin-induced nephrotoxicity in LLC-PK1 cells by blocking the JNK-p53-caspase-3 signaling cascade.

Synchronous multicentric small hepatocellular carcinomas: defining the capsule on high-frequency intraoperative ultrasonography with pathologic correlation.

PURPOSE: The aim of this study was to define the capsules of synchronous multicentric small hepatocellular carcinomas (HCCs) with use of high-frequency intraoperative ultrasonography (IOUS). METHODS: Among the 131 consecutive patients undergoing hepatic resection and high-frequency IOUS for HCC, 16 synchronous multicentric small HCCs in 13 patients were histologically diagnosed in the resected specimens. High-frequency IOUS and pathologic findings of these lesions were compared, with particular focus on the presence and appearance of the capsule in or around each lesion. RESULTS: Synchronous multicentric small HCCs were pathologically classified into distinctly nodular (n=12) or vaguely nodular (n=4) types. All 12 distinctly nodular HCCs including six subcentimeter lesions showed detectable capsules on high-frequency IOUS and pathology. The capsules appeared as a hypoechoic rim containing hyperechoic foci (n=6), hypoechoic rim (n=5), or hyperechoic rim (n=1) with varying degrees of coverage around each lesion. Histologically, the capsules were composed of a combination of one to four layers consisting of a fibrous capsule, peritumoral fibrosis, prominent small vessels, and entrapped hepatic parenchyma. CONCLUSION: Synchronous multicentric small HCCs with distinctly nodular type, even at subcentimeter size, can show capsules with varying coverage and diverse echogenicity on high-frequency IOUS.

Incidental gallbladder cancer after routine cholecystectomy: when should we suspect it preoperatively and what are predictors of patient survival?

PURPOSE: In about 1% of cases, incidental gallbladder cancers (iGBC) are found after routine cholecystectomy. The aim of this study is to compare clinical features of iGBC with benign GB disease and to evaluate factors affecting recurrence and survival. METHODS: Between January 1998 and March 2014, 4,629 patients received cholecystectomy and 73 iGBC patients (1.6%) were identified. We compared clinical features of 4,556 benign GB disease patients with 73 iGBC patients, and evaluated operative outcomes and prognostic factors in 56 eligible patients. RESULTS: The iGBC patients were older and concomitant diseases such as hypertension and anemia were more common than benign ones. And an age of more than 65 years was the only risk factor of iGBC. Adverse prognostic factors affecting patients' survival were age over 65, advanced histology, lymph node metastasis, and lymphovascular invasion on multivariate analysis. Age over 65 years, lymph node involvement, and lymphovascular invasion were identified as unfavorable factors affecting survival in subgroup analysis of extended cholecystectomy with bile duct resection (EC with BDR, n = 22). CONCLUSION: Prior to routine cholecystectomy, incidental GB cancer should be suspected especially in elderly patients. And advanced age, lymph node metastasis, and lymphovascular invasion are important prognostic factors in EC with BDR cohorts.

Protective Effect of Artemisia asiatica Extract and Its Active Compound Eupatilin against Cisplatin-Induced Renal Damage.

The present study investigated the renoprotective effect of an Artemisia asiatica extract and eupatilin in kidney epithelial (LLC-PK1) cells. Although cisplatin is effective against several cancers, its use is limited due to severe nephrotoxicity. Eupatilin is a flavonoid compound isolated from the Artemisia plant and possesses antioxidant as well as potent anticancer properties. In the LLC-PK1 cellular model, the decline in cell viability induced by oxidative stress, such as that induced by cisplatin, was significantly and dose-dependently inhibited by the A. asiatica extract and eupatilin. The increased protein expressions of phosphorylated JNK and p38 by cisplatin in cells were markedly reduced after A. asiatica extract or eupatilin cotreatment. The elevated expression of cleaved caspase-3 was significantly reduced by A. asiatica extract and eupatilin, and the elevated percentage of apoptotic cells after cisplatin treatment in LLC-PK1 cells was markedly decreased by cotreatment with A. asiatica extract or eupatilin. Taken together, these results suggest that A. asiatica extract and eupatilin could cure or prevent cisplatin-induced renal toxicity without any adverse effect; thus, it can be used in combination with cisplatin to prevent nephrotoxicity.

Synthesis of apoptotic chalcone analogues in HepG2 human hepatocellular carcinoma cells.

Eight chalcone analogues were prepared and evaluated for their cytotoxic effects in human hepatoma HepG2 cells. Compound 5 had a potent cytotoxic effect. The percentage of apoptotic cells was significantly higher in compound 5-treated cells than in control cells. Exposure to compound 5 for 24h induced cleavage of caspase-8 and -3, and poly (ADP-ribose) polymerase (PARP). Our findings suggest that compound 5 is the active chalcone analogue that contributes to cell death in HepG2 cells via the extrinsic apoptotic pathway.

Protective effect of artemisia asiatica extract against renal ischemia-reperfusion injury in mice.

OBJECTIVES: An extract of Artemisia asiatica was reported to possess antioxidative and cytoprotective actions in various experiments. Ischemia-reperfusion injury remains a major problem in kidney transplant, and the inflammatory response to ischemia-reperfusion injury exacerbates the resultant renal injury. In the present study, we investigated whether an extract of Artemisia asiatica exhibits renoprotective effects against ischemia-reperfusion-induced acute kidney injury in mice. MATERIALS AND METHODS: Renal ischemia-reperfusion injury was induced in male C57BL/6 mice by bilateral renal pedicle occlusion for 30 minutes followed by reperfusion for 48 hours. An extract of Artemisia asiatica (100 mg/kg oral) was administered 4 days before ischemia-reperfusion injury. Sham operation and phosphate-buffered saline were used as controls. Blood and renal tissues were evaluated at 48 hours after ischemiareperfusion injury. RESULTS: Treatment with an extract of Artemisia asiatica significantly decreased blood urea nitrogen, serum creatinine levels, and kidney tubular injury (P ≤ .05). Western blot showed that an extract of Artemisia asiatica significantly increased the level of heme oxygenase-1 and B-cell lymphoma 2 at 48 hours after ischemia-reperfusion injury and attenuated the level of inducible nitric oxide synthase. CONCLUSIONS: An extract of Artemisia asiatica improves acute renal ischemia-reperfusion injury by reducing inflammation and apoptosis. These findings suggest that an extract of Artemisia asiatica is a potential therapeutic agent against acute ischemia-induced renal damage.

Protective effect of tetrahydrocurcumin against cisplatin-induced renal damage: in vitro and in vivo studies.

The adverse effects of anticancer drugs can prompt patients to end their treatment despite the efficacy. Cisplatin is a platinum-based molecule widely used to treat various forms of cancer, but frequent and long-term use of cisplatin is limited due to severe nephrotoxicity. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin on cisplatin-induced kidney damage, oxidative stress, and inflammation to evaluate its possible use in renal damage. Cisplatin-induced LLC-PK1 renal cell damage was significantly reduced by tetrahydrocurcumin treatment. Additionally, the protective effect of tetrahydrocurcumin on cisplatin-induced oxidative renal damage was investigated in rats. Tetrahydrocurcumin was orally administered every day at a dose of 80 mg/kg body weight for ten days, and a single dose of cisplatin was administered intraperitoneally (7.5 mg/kg body weight) in 0.9 % saline on day four. The creatinine clearance levels, which were markers of renal dysfunction, in cisplatin-treated rats were recovered nearly back to normal levels after administration of tetrahydrocurcumin. Moreover, tetrahydrocurcumin exhibited protective effects against cisplatin-induced oxidative renal damage in rats by inhibiting cyclooxygenase-2 and caspase-3 activation. These results collectively provide therapeutic evidence that tetrahydrocurcumin ameliorates renal damage by regulating inflammation and apoptosis.

Synergistic effect of curcumin on epigallocatechin gallate-induced anticancer action in PC3 prostate cancer cells.

Epigallocatechin gallate (EGCG) and curcumin are well known to naturally-occurring anticancer agents. The aim of this study was to verify the combined beneficial anticancer effects of curcumin and EGCG on PC3 prostate cancer cells, which are resistant to chemotherapy drugs and apoptosis inducers. EGCG showed weaker inhibitory effect on PC3 cell proliferation than two other prostate cancer cell lines, LNCaP and DU145. Co-treatment of curcumin improved antiproliferative effect of EGCG on PC3 cells. The protein expressions of p21 were significantly increased by the co-treatment of EGCG and curcumin, whereas it was not changed by the treatment with each individual compound. Moreover, treatments of EGCG and curcumin arrested both S and G2/M phases of PC3 cells. These results suggest that the enhanced inhibitory effect of EGCG on PC3 cell proliferation by curcumin was mediated by the synergic up-regulation of p21-induced growth arrest and followed cell growth arrest.

Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells.

Because of poor prognosis, clinical treatment of triple-negative (TN) breast cancer remains the most challenging factor in cancer treatment. Extensive research into alternative cancer therapies includes studying the naturopathic effects of the medicinal herb ginseng. This study investigates the anti-neoplastic properties of ginseng sapogenins and the derivatives: (1) (20(S)-protopanaxadiol (PPD), (2) 20(S)-protopanaxatriol), (3) (20(S)-dihydroprotopanaxadiol, and (4) 20(S)-dihydroprotopanaxatriol). These compounds were found to prevent the proliferation of MDA-MB-231 human breast cancer cells. PPD was the most potent inhibitor, exhibiting an IC50 (5.87 µM) comparable to that of the chemotherapeutic drug taxol. Furthermore, PPD induced dose-dependent cleavage of caspase-8, caspase-3, and PARP in MDA-MB-231 cells. Thus, we propose that PPD acts as anti-cancer agent by stimulating caspase-dependent apoptosis in breast cancer cells.

Management of postoperative bilomas and biliary injuries associated with laparoscopic cholecystectomy with intrabiliary ethanol ablation and micro-coil embolization.

Laparoscopic cholecystectomy (LC) is the treatment of choice for gallbladder stones. One of the major complications associated with LC is bile duct injury; ligation or cutting of a bile duct can result in significant segmental biliary obstruction with cholangitis or bile leak, which can progress to bile peritonitis or biliary fistula. Most postoperative bilomas and bile leaks can be treated by percutaneous drainage and decompression of the biliary system by endoscopic stent placement or nasobiliary drainage. When conservative methods fail despite prolonged drainage, selective intrahepatic biliary ethanol and micro-coil embolization may be an alternative treatment. We report three successful cases where postoperative bilomas associated with laparoscopic cholecystectomy have been managed with intrabiliary ethanol ablation and micro-coil embolization.

Synthesis of diethylamino-curcumin mimics with substituted triazolyl groups and their sensitization effect of TRAIL against brain cancer cells.

A newly designed curcumin mimic library (11a-11k) with 2-ethylamino groups in a chalcone structure and variously substituted triazole groups as side chains was synthesized using the Huisgen 1,3-cycloaddition reaction between various alkynes (a-k) and an intermediate (10), with CuSO4 and sodium ascorbate in a solution mixture of chloroform, ethanol, and water (5:3:1) at room temperature for 5h. In the lactate dehydrogenase (LDH) release assay involving co-treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and/or synthetic curcumin derivatives using TRAIL-resistant human CRT-MG astroglioma cells, the novel curcumin mimic library was found to effectively stimulate the cytotoxicity of TRAIL, causing mild cytotoxicity when administered alone. In particular, 11a and 11j are promising candidates for TRAIL-sensitizers with potential use in combination chemotherapy for brain tumors.

Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-ß1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance.

The epithelial-mesenchymal transition (EMT) is a pivotal cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which, in turn, promotes the metastatic potential of cancer. Ginseng is a perennial plant belonging to the genus Panax that exhibits a wide range of pharmacological and physiological activities. Ginsenosides 20-Rg3, which is the active component of ginseng, has various medical effects, such as anti-tumorigenic, anti-angiogenesis, and anti-fatiguing activities. In addition, ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are epimers, and this epimerization is produced by steaming. However, the possible role of 20(S)-Rg3 and 20(R)-Rg3 in the EMT is unclear. We investigated the effect of 20(S)-Rg3 and 20(R)-Rg3 on the EMT. Transforming growth factor-beta 1 (TGF-ß1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the repressive role of 20(S)-Rg3 and 20(R)-Rg3 in lung cancer migration, invasion, and anoikis resistance, we investigated the potential use of 20(S)-Rg3 and 20(R)-Rg3 as inhibitors of TGF-ß1-induced EMT development in A549 lung cancer cells in vitro. Here, we show that 20(R)-Rg3, but not 20(S)-Rg3, markedly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker vimentin during initiation of the TGF-ß1-induced EMT. 20(R)-Rg3 also inhibited the TGF-ß1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, 20(R)-Rg3 markedly inhibited TGF-ß1-regulated matrix metalloproteinase-2 and activation of Smad2 and p38 mitogen activated protein kinase. Taken together, our findings provide new evidence that 20(R)-Rg3 suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-ß1-induced EMT.

Anticarcinogenic effects of products of heat-processed ginsenoside Re, a major constituent of ginseng berry, on human gastric cancer cells.

Ginsenoside Re is a triol type triterpene glycoside and is abundantly present in ginseng berry. In the present study, we verified that ginsenoside Re can be transformed into less-polar ginsenosides, namely, Rg2, Rg6, and F4, by heat-processing. The products of heat-processed ginsenoside Re inhibited phosphorylation of CDK2 at Thr160 by upregulation of p21 level, resulting in S phase arrest. The products of heat-processed ginsenoside Re also activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Concurrently, alteration of mitochondrial factors such as Bcl-2 and Bax was also observed. Moreover, pretreatment with Z-VAD-fmk abrogated caspase-8, -9, and -3 activations by the products of heat-processed ginsenoside Re. We further confirmed that the anticancer effects of the products of heat-processed ginsenoside Re in AGS cells are mainly mediated via generation of less-polar ginsenosides Rg6 and F4.