Toxicology Research PAPER Cite this: Toxicol. Res., 2019, 8, 560 Received 2nd May 2019, Accepted 21st May 2019 DOI: 10.1039/c9tx00103d rsc.li/toxicology-research Dendrimer-conjugated podophyllotoxin suppresses DENA-induced HCC progression by modulation of inflammatory and fibrogenic factors† Supriya Sharma, a,c Mehak, b Jyoti Chhimwal, a,c Vikram Patial * a,c and Ugir Hossain Sk* b,d Podophyllotoxin has been explored as an anticancer, antiviral, and antibacterial agent; however, its low water solubility and toxicity limit its use. In this study, the efficacy of a more soluble and less toxic poly- amidoamine (PAMAM) dendrimer-conjugated podophyllotoxin (DPODO) was evaluated against chemi- cally induced hepatocellular carcinoma (HCC) in mice. HCC was induced by giving 0.01% diethyl- nitrosamine (DENA) in drinking water for 16 weeks. The HCC-induced mice were treated with 10 or 20 mg per kg body weight DPODO. The DENA administration led to HCC development, characterized by anisocytosis, karyomegaly, inflammation and degenerative changes in the liver. The DPODO treatment at 10 mg and 20 mg doses significantly reduced the histopathological changes in liver tissue. The DPODO treatment also significantly lowered the levels of inflammatory markers IL-6 and NF-κB in serum and tissue, respectively. Further, the treatment also significantly reduced fibrous tissue deposition in the liver, which was further confirmed by the reduced mRNA levels and tissue expression of fibrogenic markers TGF-β and α-SMA in the liver. The results of the present study indicate that DPODO treatment suppresses the progression of HCC by modulating the inflammatory and fibrogenic factors, which play important roles in HCC development. 1. Introduction Liver cancer is estimated to be the fifth most common cancer globally, accounting for up to 80% of all cancer cases. 1 The increasing incidence of hepatocellular carcinoma (HCC) makes it the second leading cause of death. 2 The prime factors responsible for HCC include viral infection (hepatitis B and C), the consumption of mycotoxin-contaminated food grains, industrial toxicants, and excessive consumption of alcohol. 3 DENA is a commonly used carcinogen for investigating the progression of HCC in experimental animals. It is one of the environmental toxicants present in cosmetics, tobacco smoke, and processed dairy and meat products. 4 DENA acts by produ- cing nitric oxide (NO), leading to hypoxic tissue condition, suppression of deoxyribonucleotide synthesis, and thus dis- turbing protein synthesis. 5 Aggressive treatment strategies for liver cancer are limited, and the development of drug resis- tance makes HCC treatment a great challenge. 1 Further, the prognosis of the disease remains poor due to the high rates of hepatic carcinoma relapse. Chemotherapy is one of the approaches to cure HCC, but the use of chemotherapeutic agents is also associated with many harmful effects, routing towards mortality. 6 Podophyllotoxin is a naturally occurring cyclolignan syn- thesized through the shikimic acid pathway and mainly iso- lated from Podophyllum peltatum Linn. and P. hexandrum. It possesses anticancer and immunosuppressive properties, along with antiviral effects against influenza, warts, and herpes viruses. 7 However, due to its toxic side effects, extensive structural modifications have been performed on the com- pound over the years. 8 Etoposide, one of the derivatives of podophyllotoxin, has been reported to have high therapeutic activity, especially in the treatment of leukemia, malignant lymphoma and testicular carcinoma. 9 It has been reported to reversibly bind with tubulin, preventing microtubule for- † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c9tx00103d a Pharmacology and Toxicology Laboratory, Institute of Himalayan Bioresource Technology, Palampur, H.P., India. E-mail: vikrampatial@ihbt.res.in, drvikrampatial@yahoo.in b Natural Products Chemistry and Process Development Division, Institute of Himalayan Bioresource Technology, Palampur, H.P., India c Academy of Scientific & Innovative Research, Institute of Himalayan Bioresource Technology, Palampur, H.P., India d Clinical and Translational Research, Chittaranjan National Cancer Institute, Kolkata 700026, India. E-mail: uhocju@gmail.com 560 | Toxicol. Res. , 2019, 8, 560–567 This journal is © The Royal Society of Chemistry 2019 Downloaded from https://academic.oup.com/toxres/article/8/4/560/5555793 by guest on 28 December 2022