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Published on: September 25, 2018
Cytotoxicity of curcumin derivatives in ALK positive non-small cell lung cancer
Abigail R Bland1, Rebekah L Bower1, Mhairi Nimick1
1Department of Pharmacology & Toxicology, School of Biomedical Sciences, Department of Chemistry, University of Otago, Dunedin, New Zealand.
Abstract:
Non-small cell lung cancer with ALK rearrangements can be targeted effectively with ALK inhibitors such as crizotinib. However, cancer progression typically occurs within a year as drug resistance develops. One strategy to overcome this drug resistance is to determine if novel cytotoxic agents retain the ability to kill lung cancer cells that have developed ALK inhibitor resistance. We therefore examined curcumin, a drug with anticancer properties, and 2 s-generation curcumin derivatives (1-methyl-3,5-bis[(E)-4-pyridyl) methylidene]-4-piperidone (RL66) and 1-isopropyl-3,5-bis[(pyridine-3-yl) methylene]piperidin-4-one (RL118)) in lung cancer cell lines. The cytotoxicity of curcumin, RL66, and RL118 were tested in both ALK+ lung cancer cells (H3122), crizotinib resistant ALK+ cells (CR-H3122) and ALK- lung cancer cells (A549), both alone and in combination with crizotinib. ALK+ cells were 2-3x more sensitive to RL66 and RL118 than ALK- cells, with the drugs' eliciting IC50 values in the range of 0.7-1 μM in H3122 cells. Retained cytotoxic potency of the curcumin derivatives in crizotinib resistant cells indicated that mechanisms of resistance to the two drug types are independent, with resistance to ALK inhibitors not necessarily causing cross-resistance to curcumin derivatives. This was further corroborated by drug combination analysis where the effect of the drugs in combination was consistent with Bliss additivity, consistent with independent targets for crizotinib and curcumin derivatives. Results from Western blotting showed that RL118 (2 μM) inhibited p-ALK/ALK by ~50%, which was not as potent as the 90% inhibition elicited by crizotinib (0.25 μM). Since this is the primary mechanism of crizotinib cytotoxicity this provides further evidence of independent mechanisms of toxicity.
Insights
Novel curcumin derivatives show potent cytotoxicity against ALK-positive lung cancer cells, even those resistant to ALK inhibitors like crizotinib. These compounds offer a promising strategy to overcome drug resistance in non-small cell lung cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements is effectively treated with ALK inhibitors, but resistance develops rapidly.
- Drug resistance in ALK-rearranged NSCLC necessitates the exploration of novel therapeutic agents with independent mechanisms of action.
Purpose of the Study:
- To evaluate the cytotoxic potential of curcumin and its second-generation derivatives (RL66 and RL118) against ALK-positive and ALK-negative NSCLC cells.
- To determine if these curcumin derivatives retain efficacy in crizotinib-resistant NSCLC cells and to elucidate their mechanisms of action in combination with crizotinib.
Main Methods:
- Cytotoxicity assays (IC50 determination) were performed on ALK-positive (H3122), crizotinib-resistant ALK-positive (CR-H3122), and ALK-negative (A549) NSCLC cell lines.
- Curcumin derivatives (curcumin, RL66, RL118) were tested alone and in combination with crizotinib.
- Western blotting was used to assess the inhibition of phosphorylated ALK (p-ALK) by the compounds.
Main Results:
- Curcumin derivatives RL66 and RL118 demonstrated significant cytotoxicity against ALK-positive cells (IC50: 0.7-1 μM), showing 2-3 times greater sensitivity compared to ALK-negative cells.
- The curcumin derivatives maintained their cytotoxic potency in crizotinib-resistant cells, indicating independent mechanisms of action and no cross-resistance.
- Combination studies suggested additive effects (Bliss additivity) between crizotinib and curcumin derivatives, supporting distinct cellular targets.
- RL118 inhibited p-ALK/ALK by approximately 50% at 2 μM, which is less potent than crizotinib's 90% inhibition at 0.25 μM, further supporting independent mechanisms.
Conclusions:
- Curcumin derivatives RL66 and RL118 are effective cytotoxic agents against ALK-positive NSCLC cells, including those resistant to crizotinib.
- The independent mechanisms of action of curcumin derivatives and ALK inhibitors offer a viable strategy to overcome drug resistance in NSCLC.
- These findings highlight the therapeutic potential of curcumin derivatives as a new class of agents for treating ALK-rearranged NSCLC, particularly in cases of acquired resistance.
