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Updated: Oct 18, 2025
Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
Published on: May 14, 2018
Synthesis of small molecules targeting paclitaxel-induced MyD88 expression in triple-negative breast cancer cell
Khor Poh Yen1, Johnson Stanslas2, Tianshu Zhang3
1Faculty Pharmacy and Health Sciences, Universiti Kuala Lumpur, Royal College of Medicine Perak, 3, Jalan Greentown, 30450 Ipoh, Perak, Malaysia; Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
Abstract:
Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4- cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.
Insights
New compounds combat paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC). A trifluoromethyl-substituted compound synergized with PTX, inhibiting growth in TLR4-positive and TLR4-negative TNBC cells by targeting the TLR4/MyD88 pathway.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) is linked to toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) overexpression.
- Activation of the TLR4/MyD88 signaling pathway is a key mechanism driving PTX chemoresistance in TNBC.
Purpose of the Study:
- To synthesize and evaluate novel small molecule compounds as inhibitors of the TLR4/MyD88 pathway.
- To identify compounds that can overcome PTX chemoresistance in TNBC when used in combination therapy.
Main Methods:
- Synthesis of novel small molecule compounds.
- In vitro testing of compounds in combination with PTX against TNBC cell lines (MDA-MB-231TLR4+ and HCCTLR4-).
- Fluorescence titration and molecular docking analysis to assess compound binding to MD2, a TLR4 accessory protein.
Main Results:
- A trimethoxy-substituted compound reduced MyD88 and enhanced PTX activity in TLR4-positive TNBC cells.
- A trifluoromethyl-substituted compound demonstrated synergistic growth inhibition with PTX in both TLR4-positive and TLR4-negative TNBC cells.
- Both synthesized compounds exhibited favorable binding affinities to MD2, crucial for TLR4/MyD88 pathway activation.
Conclusions:
- The trifluoromethyl-substituted compound is a promising candidate for overcoming PTX chemoresistance in diverse TNBC subtypes.
- Targeting the TLR4/MyD88 pathway, specifically through MD2 interaction, offers a viable strategy to enhance chemotherapy efficacy in TNBC.
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