Abstract
Carboplatin, a second-generation platinum agent, has been used as a cancer therapy for decades and exhibits strong anti-tumor activity. However, the wide application of carboplatin is largely limited due to its side effects, especially myelosuppression. Here, we combined carboplatin with curcumin, a natural product that improves tumor-induced anemia, for the treatment of fibrosarcoma to improve the side effects of carboplatin. We first examined the synergistic and attenuated effects of the two agents in a T241-bearing mouse model. The combination therapy caused no obvious synergistic effect, but curcumin significantly improved the survival rate of carboplatin-treated mice. Histologic analysis of the kidney and bone marrow revealed that curcumin improved carboplatin-induced myelosuppression but did not affect the kidney. To determine the mechanism involved, we introduced a probe derived from curcumin to identify its targets in bone marrow cells and the results provided us a clue that curcumin might affect the DNA repair pathway. Western blot analysis revealed that curcumin up-regulated BRCA1, BRCA2 and ERCC1 expression in bone marrow. In conclusion, curcumin attenuates carboplatin-induced myelosuppression by activating the DNA repair pathway in bone marrow cells.
Highlights
Platinum-based drugs, the most commonly used chemotherapeutic agents, have been used for many years for the treatment of several types of cancer, including ovarian, cervical, head and neck, and non-small-cell lung cancer[1,2]
Together with our previous finding that curcumin suppressed VEGF production from tumor cells and inhibited the VEGF-VEGFR2 signaling pathway[20], we inferred that the combination of curcumin and carboplatin may result in an improved life span compared to treatment with carboplatin alone
As carboplatin and curcumin both exhibit anti-cancer activity[38,39], we first examined the synergistic effect of the two agents on tumor growth; there was no obvious synergistic effect
Summary
Platinum-based drugs, the most commonly used chemotherapeutic agents, have been used for many years for the treatment of several types of cancer, including ovarian, cervical, head and neck, and non-small-cell lung cancer[1,2]. Platinum-based drugs exhibit strong anticancer activity, their usage is largely limited due to their serious side effects[3]. Carboplatin-induced myelosuppression leads to anemia in patients[9,10] and largely limits carboplatin’s therapeutic effect of prolonging life span of tumor-bearing patients. The effect of curcumin on platinum-based drugs induced toxicity has been largely reported. Considering curcumin’s anti-cancer activity and improvement in hematopoiesis, the combination of carboplatin and curcumin would likely be a good treatment option for cancer therapy. As both agents exhibit anticancer activity, the combination may lead to improved therapeutic effects. We will examine the effects of the combined drug therapy on tumor growth, kidney and bone marrow in T241-bearing mice and explore the mechanisms involved with a chemical proteomics approach
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