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.
Highlights
Quality of life for most cancer-bearing patients becomes severely compromised after chemo- and/or radiotherapy, due to the numerous side effects associated with these aggressive treatments [1]
Casiopeina II-gly (CasII-gly) was used as a non-canonical, experimental anti-cancer drug and showed greater potency (IC50 = 1.5 μM) for inhibiting HeLa cell proliferation compared to non-steroidal anti-inflammatory drug (NSAID) and the other canonical chemotherapy drugs (Table 1)
All the IC50 values obtained here were within the range of values reported for the same drugs in HeLa cells [43,44,45,46]
Summary
Quality of life for most cancer-bearing patients becomes severely compromised after chemo- and/or radiotherapy, due to the numerous side effects (hematological, gastrointestinal, hepatic, and/or renal damages) associated with these aggressive treatments [1]. To minimize these unwanted adverse effects, several approved clinical protocols that include combining two or more drugs are under development, with the rationale of improving their efficacy whilst decreasing toxic side effects from each drug used alone. The aim is to target two or more different essential cancer cell processes such as cell proliferation, signaling, and/or metabolism In this regard, the repurposing of approved drugs could be a promising alternative anti-cancer strategy. The reason is that the careful selection of such drugs may have advantages in that (i) they should show less side effects; (ii) they may have unconventional but effective targets in tumor cells; and (iii) their use may decrease the overall cost and time associated with the development of brand-new chemotherapeutics [7,8]
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