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.

The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical application. β-elemene is a natural sesquiterpene with potent anti-cancer ability, and also it is renowned for its plant-origin, safety and the additive effect with traditional therapies, which prompt us to explore its potential to co-operate with TKIs to achieve greater therapeutic efficacy. Impressively, our study demonstrates that, elemene, in combination of gefitinib, displayed a significantly higher activity in inhibiting lung cancer cellular proliferation, migration and invasion. More importantly, combinative treatment profoundly impaired the epithelial to mesenchymal transition (EMT), the stem-like properties and the self-renewal capacity of lung cancer cells, and hence impeded the in vivo tumor development. We also reveal that the synergistic anti-tumor effect of elemene and gefitinib was largely mediated their regulation of enhancer of zeste homolog 2 (EZH2), an oncogenic histone methyltransferase and gene transcriptional regulator. Thus, our data indicate that combinative treatment of elemene and gefitinib has greater anti-neoplastic activity and greater efficacies in targeting cancer stem-like properties, mainly through regulating the malignant gene modifier and hence the subsequent effector molecules required for cancer progression. The findings may have potential implications for treating aggressive and resistant lung cancers.

Background/Aims: The effects of zinc signaling on proliferation or apoptosis of leukemia cells remain elusive. In the present study, we used N, N, N’, N’-tetrakis-(2-pyridylmethyl)-ethylene-diamine (TPEN), a membrane-permeable zinc chelator, to evaluate the effect of zinc depletion on survival and apoptosis of NB4 acute promyelocytic leukemia (APL) cells. Methods: The pro-apoptotic effects of TPEN on NB4 cells were examined by flow cytometry, and observed using an optical microscope. Intracellular labile zinc, nitric oxide (NO) or reactive oxygen species (ROS) changes caused by TPEN were measured by flow cytometry. We then explored possible roles of the crosstalk between intracellular labile zinc signaling and nitric oxide signaling in TPEN-triggered apoptosis. Results: we found that TPEN induced apoptosis in NB4 APL cells in a dosage-dependent manner. We further demonstrated that TPEN triggered apoptosis by attenuating intracellular zinc and nitric oxide signaling in NB4 cells. Both exogenous zinc supplement and the nitric donor sodium nitroprusside (SNP) pre-incubation reversed TPEN-mediated inhibition of intracellular NO and Zn²⁺ signaling, and rescued NB4 cells from apoptosis. Conclusion: These results suggest for the first time that crosstalk between zinc signaling and nitric oxide pathway is essential for the survival of NB4 cells. TPEN induces apoptosis in NB4 cells via negatively regulating intracellular NO and Zn²⁺ signaling. Our in vitro data suggest that zinc depletion by TPEN may be a potential therapeutic strategy for APL.

Lithium, a trace element important for fetal health and development, is considered a metal drug with a well-established clinical regime, economical production process, and a mature storage system. Several studies have shown that lithium affects tumor development by regulating inositol monophosphate (IMPase) and glycogen synthase kinase-3 (GSK-3). Lithium can also promote proliferation and programmed cell death (PCD) in tumor cells through a number of new targets, such as the nuclear receptor NR4A1 and Hedgehog-Gli. Lithium may increase cancer treatment efficacy while reducing side effects, suggesting that it can be used as an adjunctive therapy. In this review, we summarize the effects of lithium on tumor progression and discuss the underlying mechanisms. Additionally, we discuss lithium’s limitations in antitumor clinical applications, including its narrow therapeutic window and potential pro-cancer effects on the tumor immune system.