Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model
Mol Cancer Ther. 2009;8(4):959-70
Multiple myeloma is a late-stage B-cell malignancy characterized by the infiltration of malignant plasma cells in bone marrow and is associated with high monoclonal protein in the blood. Multiple myeloma can occur de novo or can evolve from benign monoclonal gammapathy of undetermined significance that involves low levels of bone marrow plasmacytosis and monoclonal protein. Each year approximately 1% of patients with monoclonal gammapathy of undetermined significance develop multiple myeloma.
Currently, high-dose chemotherapy and stem cell transplantation are the standard treatments followed for multiple myeloma. Although several newer drugs have been approved recently, treatment for multiple myeloma yet remains as a challenge.
Resistance to chemotherapy in multiple myeloma is not yet clear but has been evidenced that NF-κB may play a major role in pathogenesis of multiple myeloma. Thus, compounds like Curcumin, known to inhibit the activation of NF-κB, are effective against chemoresistance in multiple myeloma cells.
Objective:
To investigate whether Curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with multiple myeloma, in vitro and in xenograft model in nude mice.
Study Design:
Various parameters like antiproliferative effects of Curcumin, NF-κB activation in myeloma cell lines and tumor samples, and potentiation of apoptotic effects of bortezomib and thalidomide in the presence of Curcumin in multiple myeloma cells were evaluated in vitro
In vivo Study:
Male athymic nu/nu mice (4 weeks old) were implanted with U266 cells to induce multiple myeloma
Animals were randomized into treatment groups (n=5), post one week of implantation, based on the tumor volume
Group I (control) was treated with corn oil (100 μL, orally, daily) and saline (100 μL, orally, weekly), group II was treated with Curcumin alone (1 g/kg, orally, daily), group III was treated with bortezomib alone (0.25 mg/kg, 100 μL, i.p., weekly) and group IV was treated with a combination of Curcumin (1 g/kg, orally, daily) and bortezomib (0.25 mg/kg, 100 μL, weekly)
Treatment was continued for up to 20 days from the date of randomization (day 0)
The tumor volume was measured on every 5 days, and after 25 days of randomization, mice were killed and tumors were carefully excised and measured to calculate tumor volume
Results and Discussion:
Irrespective of whether a cell line is a sensitive or resistant to a conventional chemotherapeutic agent, a dose- and time-dependent antiproliferative effect was observed when treated with Curcumin
Curcumin significantly potentiated the apoptotic effect of bortezomib and thalidomide when U266 cells were treated in combination, from 25% to 85% and from 10% to 75%, respectively
Curcumin also potentiated the inhibitory effect of bortezomib and thalidomide on NF-κB activation in multiple myeloma cells
Curcumin inhibited the expression of NF-ĸB-regulated gene products in multiple myeloma cells as well
In human multiple myeloma xenograft model, curcumin alone as well as bortezomib alone significantly decreased the tumor volume
Similarly, Curcumin and bortezomib combination group also showed more significant decrease in tumor volume when compared to bortezomib alone group and in the control group at day 25 after treatment
Curcumin and bortezomib combination group showed much more effective reduction in the tumor volume when examined for tumor volume on different days, compared with either agent alone
Conclusion
Overall, Curcumin potentiated effects of bortezomib and thalidomide, and overcame chemoresistance as well as sensitized multiple myeloma cells by down-regulating NF-κB and NF-κB-regulated gene products.
