Minnelide, a novel drug for pancreatic and liver cancer

Abstract

Background: Pancreatic cancer is the 10th leading cause of all new cancer cases for men and the fourth leading cause of death across genders, having very poor prognosis and survival rates. The current standard of care Gemcitabine fails to add any survival benefit for this disease (www.cancer.gov). Though the incidence of pancreatic cancer is found to be higher in developed countries, the aggressive biology of the cancer, its high rate of recurrence and chemo-resistance make it a formidable disease in all parts of the globe. Hepatocellular carcinoma (HCC) or liver cancer, on the other hand affects almost 750,000 people world wide with 84% of the cases coming from underdeveloped or developing countries

Results: Our studies show that Minnelide, a water soluble pro-drug of triptolide (active compound from a chinese herb) is very effective against a number of malignant diseases.

Conclusion: The current study discusses the efficacy of this compound in pancreatic and liver cancer.

Keywords: Animal models; Hepatocellular carcinoma; Minnelide; Pancreatic cancer; Translational study; Triptolide.

Figure 1

(A). Triptolide the active drug reduced cell viability in pancreatic cancer cell line MIA-PACA2. Pancreatic cancer cells were treated with indicated doses of triptolide. Cell viability was assessed by MTT based assay. The X-axis shows the treatment doses while Y-axis shows the cell viability normalized to control. Minnelide has been very effective in pre-clinical models of pancreatic cancer. 200,000 S2-013 cells were injected orthotopically into the tail of the pancreas of athymic nude mice. Treatment with 0.42mg/kg Minnelide (administered daily) was started after 2 weeks of tumor cell injection and continued for 30 days. Tumor weight (B) and tumor volume (C) was measured at the end of study following necropsy. Survival study was performed using pancreatic cancer cell line AsPC-1. 200,000 AsPC1 cells were implanted orthotopically into the tail of the pancreas. Treatment with 0.42mg/kg Minnelide (administered daily) was started after 15 days of tumor cell injection. Median survival of Saline group was 36 days, while all the animals in the Minnelide group survived till the end of study. Further, Minnelide was discontinued after 100 days of treatment (D/C), and the animal were kept under daily observation till the end of study. Tumors did not recur even on discontinuing treatment (D). Resected pancreatic tumor tissue from patients undergoing surgery were implanted subcutaneously in the flank of NOD/SCID mice. Once tumors were ~350mm³, treatment was started with 0.42mg/kg Minnelide(administered daily). Once the tumors in animals of the saline group reached 1000mm³, treatment was started with 0.42mg/kg body weight of animals (administered daily). Treatment of a patient tumor derived xenograft with Minnelide shows increased survival (E). (Figure 1D and E are adapted from our original manuscript Chugh et al Sci. Trans. Med. 2012, and the review article Saluja AK, Dudeja V. Relevance of animal models of pancreatic cancer and pancreatitis to human disease. Gastroenterology 2013; 144:1194-8) * indicated statistically significant data with a p value<0.005; D/C= discontinued; censored data indicate natural death (non-tumor related death) in animals.

Figure 2

Liver cancer cells Huh7 and PLC were treated with indicated doses of triptolide for 24h, 48h and 72h. Cell viability measured by MTT assay, was decreased in combination of triptolide and sorafenib treatment in hepatocellular carcinoma cells Huh7 and PLC (A). For animal experiments, Sorafenib and Minnelide was an effective combination in reducing hepatocellular carcinoma in vivo (B) Subcutaneous implants of 1×10⁶ HuH7 cell lines were injected subcutaneously in athymic nude mice. When the tumors were 200mm³ in size, the animals were randomized into 4 groups: Untreated, Minnelide (0.21mg/kg), Sorafenib (10mg/kg) and a combination of these two drugs. Tumors treated with 0.21mg/kg Minnelide and 10mg/kg Sorafenib showed an increased reduction in tumor volume compared to either drug alone. (B). * indicated statistically significant data with a p value<0.005