Effect of 1-Carbaldehyde-3,4-dimethoxyxanthone on Prostate and HPV-18 Positive Cervical Cancer Cell Lines and on Human THP-1 Macrophages.

Rui Medeiros,Fátima Cerqueira,Madalena Pinto,Bruno Horta,Joana Freitas-Silva,Francisca Dias,Jani Silva,Emília Sousa

doi:10.3390/molecules26123721

Abstract

Xanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer, and nonsolid tumor derived cancer (Jurkat) cell lines. The effect of xanthone 1 on macrophage functions was also evaluated. The effect of xanthone 1-conditioned THP-1 human macrophage supernatants on the metabolic viability of cervical and prostate cancer cell lines was determined along with its interference with cytokine expression characteristic of M1 profile (IL-1 ≤ β; TNF-α) or M2 profile (IL-10; TGF-β) (PCR and ELISA). Nitric oxide (NO) production by murine RAW264.7 macrophages was quantified by Griess reaction. Xanthone 1 (20 μM) strongly inhibited the metabolic activity of the cell lines and was significantly more active against prostate cell lines compared to HeLa (p < 0.05). Jurkat was the cell most sensitive to the effect of xanthone 1. Compound 1-conditioned IL-4-stimulated THP-1 macrophage supernatants significantly (p < 0.05) inhibited the metabolic activity of HeLa, LNCaP, and PC-3. Xanthone 1 did not significantly affect the expression of cytokines by THP-1 macrophages. The inhibiting effect of compound 1 observed on the production of NO by RAW 264.7 macrophages was moderate. In conclusion, 1-carbaldehyde-3,4-dimethoxyxanthone (1) decreases the metabolic activity of cancer cells and seems to be able to modulate macrophage functions.

Highlights

Xanthones, methoxyxanthones, have already been described by our group as possessing antitumor and immunomodulatory activities [1,2,3,4]
The antitumor activity of xanthone 1 was tested against liquid and2soofli1d1 tumors using lymphocyte (Jurkat), cervical (HeLa), and androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines
The antitumor effect of xanthone 1 at 20 μM was more evident against the prostate cancer cell line than the cervical cancer cell line, suggesting a selectivity of its antitumor effect, but no differences were observed at 10 μM

Summary

Introduction

Methoxyxanthones, have already been described by our group as possessing antitumor and immunomodulatory activities [1,2,3,4]. M1 and M2 cells have been found to be associated with tumor progression and a worse prognosis for solid tumors, such as cervical or prostate [11,12,14]. Therapy strategies targeting TAMs include decreasing macrophage density, either by cytotoxicity or inhibition of recruitment, and redirecting TAMs to an M1 phenotype [9,15,16]. The antitumor activity of xanthone 1 was tested against liquid and2soofli1d1 tumors using lymphocyte (Jurkat), cervical (HeLa), and androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. PTohuisnids itshae fTiArspt 7re3paocrtitvcaotnocre[r6n].ing the effect of xanthone 1 on macrophage function Tanodstnuidtryictohxeidinete(NrfeOr)enpcreodouf cxtaionnthboynJe7174omn amcarocrpohpahgaegse[1f]u.nction, the expression of cytokine 1c-hcaarrabcateldrieshtiycdoef-3M,41-d(IimL-e1tβhoaxnydxTanNtFh-oαn)ea(n1d) (MFi2gu(TreGF1)-βw1aasnpdrIeLv-i1o0u)splyhesynnotyhpeseiszebdy TbyHoPu-1r hguromuapn, amnadcritospahnatgiteusmwoarseefvfeacltuwataeds .eTvahleueaftfeedctuosfinxgancathnocnere c1eollnliNneOs opfroddifufecrteionnt boyrigLiPnSs-[s5t,i6m].uTlahteedstuRdAyWof2x6a4n.7thmonueri1noenmnaecurroopbhlasgteomceallrleivneawleadsthalastothteisstceodm. pTohuisnids itshae fTiArspt 7re3paocrtitvcaotnocre[r6n].ing the effect of xanthone 1 on macrophage function

Methods

Discussion

Conclusion