Anti-Algics in the Therapeutic Response of Breast and Urological Cancers

Abstract

The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients.

Keywords: bladder cancer; breast cancer; docetaxel; local anesthetics; opioids; prostate cancer.

Figure 1

Effect of (a) Lid, (b) Rop, and (c) Lev on metabolic activity of human breast cancer (MCF7), prostate cancer (LNCaP and PC3), bladder cancer (TCCSUP and HT1376), and non-malignant (MCF12A, HaCaT, and RWPE-1) cell lines. Metabolic activity was evaluated as a measure of cell proliferation, by colorimetric MTT assay, 48 h after treatment with Lid (0.3–10 mM), Rop (0.01–1 mM), or Lev (0.01–1 mM). In cases where sigmoid fitting adjustment was possible, dose–response curves were obtained (R² > 0.91) and the half maximal inhibitory concentrations (IC₅₀) were calculated. The values are given as the mean ± SEM of, at least, three independent experiments in triplicate.

Figure 2

Synergistic effects of Dtx with (a) Lid, (b) Lev, and (c) Rop in prostate cancer cells lines PC3 (left) and LNCaP (right). Metabolic activity was evaluated as a measure of cell proliferation, by colorimetric MTT assay, 48 h after treatment. Data are mean ± SEM, n = 5 independent experiments; * p < 0.05, **** p < 0.0001 significantly different from control (t-test). Combination index (CI) values were obtained for 48 h of incubation time. Bold CI values represent the most promising combination regimen.

Figure 3

Analysis of cell viability and types of cell death induced in PC3 cells after exposure to Lid (a), Rop (b), Lev (c), or Dtx alone or in combined therapy for 48 h. The results are represented in percentage (%) of cell in each subpopulation: viable (V), in early apoptosis (EA), in late apoptosis/necrosis (LA/N), and in necrosis (N). The results express the mean ± SEM of, at least, three independent experiments, in duplicate. Statistically significant differences relative to control and drugs in monotherapy are marked with * p < 0.05, ** p < 0.01, and *** p < 0.001.

Figure 4

LAs inhibit PC3 cell migration. (a) Representative images from the wound healing assay of PC3 treated with the associations of Dtx and LAs at 20× magnification. (b–d) Effect of (b) Lid, (c) Rop, or (d) Lev alone or in combined therapy after 4, 24, and 48 h of incubation. The results express the mean ± SEM of at least three independent experiments, in duplicate. Statistically significant differences relative to the drugs in monotherapy are marked with * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001.

Figure 5

LAs inhibit LNCaP cell migration. (a) Representative images from the wound healing assay of PC3 treated with the associations of Dtx and LAs at 20× magnification. (b,c) Effect of (b) Lid or (c) Lev alone or in combined therapy after 4, 24, and 48 h of incubation. The results express the mean ± SEM of at least three independent experiments, in duplicate. Statistically significant differences relative to the drugs in monotherapy are marked with * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001.