Enhanced lysosomal function is critical for paclitaxel resistance in cancer cells: reversed by artesunate.

The mechanism underlying the resistance of cancer cells to chemotherapeutic drug varies with different cancer cells. Recent evidence shows that lysosomal function is associated with drug resistance of cancer cells. Artesunate, a derivative of artemisinin, displays broad antitumor activity and direct cytotoxicity on various tumor cells. Our previous study shows that artesunate increases autophagosome accumulation, while significantly decreases autolysosome number in cancer cells, suggesting that artesunate might impair the lysosomal function. In this study, we investigated the effects of artesunate on lysosomal function and its relationship with chemotherapeutic drug resistance in cancer cells. We found that the lysosomal function was significantly enhanced in two drug-resistant (A549/TAX and A549/DDP) cells. Furthermore, we showed that the enhanced lysosomal function by overexpression of transcription factor EB (TFEB) significantly increased MCF-7 cells resistance to doxorubicin (DOX), whereas the decreased lysosomal function by TFEB-knockdown or lysosome inhibitor chloroquine increased MCF-7 cells sensitivity to DOX. Treatment of A549/TAX cells with artesunate (2.5-50 µM) dose-dependently inhibited lysosomal function and the clearance of dysfunctional mitochondria, and induced cell apoptosis. Moreover, we demonstrated that artesunate exerted more potent inhibition on the resistant (A549/TAX and MCF-7/ADR) cells with higher activity of lysosomal function. Our results suggest that artesunate or other inhibitors of lysosomal function would be potential in the treatment of cancer cells with drug resistance caused by the enhanced lysosomal function.

Application of contrast-enhanced ultrasonography after radiofrequency ablation for renal cell carcinoma: is it sufficient for assessment of therapeutic response?

PURPOSE: To assess the efficacy of contrast-enhanced ultrasonography (CEUS) with Sonovue in the evaluation of therapeutic response to radiofrequency ablation (RFA) of renal cell carcinoma (RCC). MATERIALS AND METHODS: In a recent 3 years, 63 patients (mean age, 60 years; range 26-81 years) with 64 RCCs were treated by RFA. The lesions had a diameter between 1.8 and 9.8 cm (average diameter, 3.1 cm). The indications for RFA treatment included chronic renal insufficiency (n = 10), presence of solitary kidney (n =3), bilateral renal carcinoma (BRCC) (n =2), advanced age (n =12), significant medical comorbidity (n =29) or refusal of conventional therapy (n =7). Tumors were treated by laparoscopy-assisted (n =41), open surgical (n =18) or percutaneous US guidance (n =4). Follow-up CEUS and contrast-enhanced CT were performed 1 month after treatment to assess the necrotic area. Technical success was defined as elimination of areas that enhanced at imaging within the entire tumor. RESULTS: On the 1-month CEUS and CT imaging after RFA, 62 of 64 tumors (96.9%) were successfully ablated with one session, and residual tumors were found in two RCCs. One of the two tumors was subjected to additional RFA treatment. We could not obtain a complete ablation in the other tumor of a patient with solitary kidney. The diagnostic concordance between the CEUS and 1-month follow-up CT was 100%. Sixty-one patients survived in the follow-up phase which ranged from 2 to 34 months. One patient with solitary kidney died of systemic disease progression and one patient was lost to follow-up. Of the 61 tumors without residual on both CT and CEUS after RFA, four had suspicious findings of recurrence on follow-up CEUS, and two of them were confirmed by subsequent CT examination. With CT as the reference imaging procedure in the assessment of renal tumor ablation, the sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for detecting recurrence during follow-up were 100%, 96.6%, 50%, and 100%. CONCLUSION: Despite its limitation of false-positive value, CEUS is potentially effective in assessing the therapeutic response to RFA of RCC.

Major complications after radiofrequency ablation for liver tumors: analysis of 255 patients.

AIM: To investigate the major complications after radiofrequency ablation (RFA) for the treatment of liver tumors and analyze possible risk factors that precipitate these complications. METHODS: From March 2001 to April 2008, 255 patients with liver tumors (205 male, 50 female; age range, 18-89 years; mean age, 56.0 years) who received RFA were enrolled in this study. Of these patients, 212 had hepatocellular carcinoma, 39 had metastatic liver tumors and four had cholangiocellular carcinoma. One hundred and forty eight patients had a single tumor, and 107 had multiple tumors. Maximum diameter of the tumors ranged 1.3-20 cm (mean, 5.1 cm). All patients were treated with a cooled-tip perfusion electrode attached to a radiofrequency generator (Radionics, Burlington, MA, USA). RFA was performed via the percutaneous approach (n = 257), laparoscopy (n = 7), or open surgical treatment (n = 86). The major complications related to RFA were recorded. The resultant data were analyzed to determine risk factors associated these complications. RESULTS: Among the 255 patients, 425 liver tumors were treated and 350 RFA sessions were performed. Thirty-seven (10%) major complications were observed which included 13 cases of liver failure, 10 cases of hydrothorax requiring drainage, three cases of tumor seeding, one case of upper gastrointestinal bleeding, one case of intrahepatic abscess, one case of bile duct injury, one case of cardiac arrest, and five cases of hyperglycemia. Seven patients had more than two complications. Liver failure was the most severe complication and was associated with the highest mortality. Eleven patients died due to worsening liver decompensation. Child-Pugh classification (P = 0.001) and choice of approach (P = 0.045) were related to post-treatment liver failure, whereas patient age, tumor size and number were not significant factors precipitating this complication. CONCLUSION: RFA can be accepted as a relatively safe procedure for the treatment of liver tumors. However, attention should be paid to possible complications even though the incidences of these complications are rare. Careful patient selection and the best approach choice (percutaneous, laparoscopy, or laparotomy) will help to minimize the incidence and morbidity rate of complications which occur after RFA.