Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance

Abstract

Tumor Necrosis Factor alpha (TNF-α) has been shown to be released by tumor cells in response to docetaxel, and lipopolysaccharides (LPS), the latter through activation of toll-like receptor 4 (TLR4). However, it is unclear whether the former involves TLR4 receptor activation through direct binding of the drug to TLR4 at the cell surface. The current study was intended to better understand drug-induced TNF-α production in tumor cells, whether from short-term drug exposure or in cells selected for drug resistance. ELISAs were employed to measure cytokine release from breast and ovarian tumor cells in response to several structurally distinct chemotherapy agents and/or TLR4 agonists or antagonists. Drug uptake and drug sensitivity studies were also performed. We observed that several drugs induced TNF-αrelease from multiple tumor cell lines. Docetaxel-induced cytokine production was distinct from that of LPS in both MyD88-positive (MCF-7) and MyD88-deficient (A2780) cells. The acquisition of docetaxel resistance was accompanied by increased constitutive production of TNF-αand CXCL1, which waned at higher levels of resistance. In docetaxel-resistant MCF-7 and A2780 cell lines, the production of TNF-α could not be significantly augmented by docetaxel without the inhibition of P-gp, a transporter protein that promotes drug efflux from tumor cells. Pretreatment of tumor cells with LPS sensitized MyD88-positive cells (but not MyD88-deficient) to docetaxel cytotoxicity in both drug-naive and drug-resistant cells. Our findings suggest that taxane-induced inflammatory cytokine production from tumor cells depends on the duration of exposure, requires cellular drug-accumulation, and is distinct from the LPS response seen in breast tumor cells. Also, stimulation of the LPS-induced pathway may be an attractive target for treatment of drug-resistant disease.

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood

“…Clinical trials are underway to explore the use of IV docetaxel alone or in combination with other agents against other advanced solid tumors and genitourinary cancers, including renal cell carcinoma [8]. Docetaxel stabilizes microtubule polymers, inhibiting mitosis and tumor cell proliferation and impacting inflammation and immunity [9,10]. Significant toxicities, especially neutropenia, are frequently seen in patients treated with IV docetaxel [7].…”

NT21MP negatively regulates paclitaxel-resistant cells by targeting miR‑155‑3p and miR‑155-5p via the CXCR4 pathway in breast cancer

“…MYD88 was previously reported to be pivotal in anticancer treatment via activation of the Toll-like receptor-mediated MYD88 signaling pathway in tumor biology, providing a novel potential target for cancer immunotherapy ( 38 – 42 ). Studies have reported that MYD88 is involved in the regulation of drug resistance in breast cancer cells ( 43 , 44 ). For example, using antibody microarrays, MYD88 was found to be differentially expressed as a predictive biomarker of neoadjuvant chemotherapy resistance in breast cancer ( 45 ).…”

Berberine Inhibits MDA-MB-231 Cells by Attenuating Their Inflammatory Responses

“…Expression. Breast cancer cells could boost the capacity of generating cytokines [11]. To explore the possible effects of berberine on the inflammation in breast cancer cells, LPS was used to treat these cancer cells in the next experiments.…”