Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids

Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

Radiosensitization of human pancreatic cancer by piperlongumine analogues

Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by2 months in combination with gemcitabine.However,prognosis and survival improvement remain unsatisfactory,and effective therapies are urgently needed.Piperlongumine has been demonstrated to have therapeutic potentials against various cancers.In this study,we synthesized a series of piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as effective radiosensitizers in pancreatic cancer.Two compounds enhanced the radiosensitivity of Panc-1 and SW1990 cells.In a pancreatic bi-flank xenograft tumor model,they significantly inhibited tumor growth.Piperlongumine derivatives could induce reactive oxygen species(ROS)expression and regulate the Keapl-Nrf2 protective pathway with enhancement of radiation-induced DNA damage,G2/M-phase cell cycle arrest,and apoptosis.Collectively,our data offer a proof of concept for the use of piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.