Non-Steroidal Anti-Inflammatory Drugs Increase Cisplatin, Paclitaxel, and Doxorubicin Efficacy against Human Cervix Cancer Cells

Abstract

This study shows that the non-steroidal anti-inflammatory drug (NSAID) celecoxib and its non-cyclooxygenase-2 (COX2) analogue dimethylcelecoxib (DMC) exert a potent inhibitory effect on the growth of human cervix HeLa multi-cellular tumor spheroids (MCTS) when added either at the beginning (“preventive protocol”; IC50 = 1 ± 0.3 nM for celecoxib and 10 ± 2 nM for DMC) or after spheroid formation (“curative protocol”; IC50 = 7.5 ± 2 µM for celecoxib and 32 ± 10 µM for DMC). These NSAID IC50 values were significantly lower than those attained in bidimensional HeLa cells (IC50 = 55 ± 9 µM celecoxib and 48 ± 2 µM DMC) and bidimensional non-cancer cell cultures (3T3 fibroblasts and MCF-10A mammary gland cells with IC50 from 69 to >100 µM, after 24 h). The copper-based drug casiopeina II-gly showed similar potency against HeLa MCTS. Synergism analysis showed that celecoxib, DMC, and casiopeinaII-gly at sub-IC50 doses increased the potency of cisplatin, paclitaxel, and doxorubicin to hinder HeLa cell proliferation through a significant abolishment of oxidative phosphorylation in bidimensional cultures, with no apparent effect on non-cancer cells (therapeutic index >3.6). Similar results were attained with bidimensional human cervix cancer SiHa and human glioblastoma U373 cell cultures. In HeLa MCTS, celecoxib, DMC and casiopeina II-gly increased cisplatin toxicity by 41–85%. These observations indicated that celecoxib and DMC used as adjuvant therapy in combination with canonical anti-cancer drugs may provide more effective alternatives for cancer treatment.

Inflammation and tumor progression: signaling pathways and targeted intervention

“…438,439 Furthermore, celecoxib, a specific COX2 inhibitor, increase the anti-tumor efficacy of cisplatin in cervix cancer cells, as well as in bladder cancer and gastric cancer. [440][441][442] Paclitaxel induces apoptosis by stabilizing microtubules, thereby leading to cell arrest. 442,443 In response to paclitaxel administration, a variety of inflammatory factors and signaling pathways, such as IL-1β, IL-8, IL-6, and NF-κB, can be activated.…”

“…[440][441][442] Paclitaxel induces apoptosis by stabilizing microtubules, thereby leading to cell arrest. 442,443 In response to paclitaxel administration, a variety of inflammatory factors and signaling pathways, such as IL-1β, IL-8, IL-6, and NF-κB, can be activated. [444][445][446][447] By using high doses of radiation to kill cancer cells and shrink tumors, radiotherapy is an important approach of cancer treatment.…”

Anticancer Activity and Mechanism of Action Evaluation of an Acylhydrazone Cu(II) Complex toward Breast Cancer Cells, Spheroids, and Mammospheres

“…[30] More recent results showed that another copper(II)-hydrazone ligand derived from 4-methoxybenzohydrazide with o-vanillin displayed similar IC 50 values on breast cancer cells. [25] 2.9 � 0.5 82 � 4 [29] Many scientific evidences showed that copper drugs with IC 50 values lower than 10 μM can be consideredas powerful antitumor agents toward human cancer cell lines. [8] Taking into account the kind of ligand used in this work we found that Lu et al designed and synthetized different copper (II) complexes with vanillin Schiff base derivatives and naproxen with anticancer activity on bulk and breast cancer stem cells, with a moderate activity (37.6 � 3.3 and 36.0 � 4.6 μM respectively).…”

Hyaluronic Acid-Modified and Doxorubicin-Loaded Gold Nanoparticles and Evaluation of Their Bioactivity

“…Therefore, PEG has been widely studied in the fields of controlled drug release, wound healing, and drug delivery [ 48 , 49 , 50 , 51 , 52 ]. Doxorubicin (Dox) is an anti-tumor drug that is clinically used for the treatment of acute myelogenous leukemia, acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, breast cancer, and other malignant tumors [ 53 , 54 , 55 , 56 , 57 , 58 ]. However, it displays a low utilization rate, causes severe adverse reactions, and an inability to effectively reach the sites of tumors [ 59 , 60 , 61 , 62 ].…”