Table 1.
Chemopotentiating Role of Thymoquinone Observed in Preclinical Studies.
| Chemotherapeutic Agents used in combination with TQ | Molecular mechanism of the chemotherapeutic agents | Identified melecular targets/pathways of TQ | Experimental models (Cell types) | Major outcome of TQ combination | References |
|---|---|---|---|---|---|
| Temozolomide (TMZ) | DNA damage through alkylation and cell cycle arrest at G2/M phase | Transcrictional inhibition of autophagy promoting genes (beclin-1 and ATG-7) | (In vitro) GBM cancer (U87MG cell line) | Synergistic effect in cell growth inhibition and apoptosis induction | Pazhouhi et al., 2016; Khazaei and Pazhouhi, 2017; |
| Cisplatin | Induction of DNA damage through Pt-mediated DNA crosslinking (Alkylating-like mechanism) | Inhibition of NF-κB activation (decresed level of phosphorylated p65 in nucleus), Downregulation of pro-angiogenic factor (VEGF), oncogenic protein (c-Myc), antiapoptotic protein (Bcl-2), Chemo-protective effect | (In vitro) Colon cancer (COLO205, HCT116), (In vivo) Syngeneic mouse model of ovarian cancer (ID8-NGL cells), (In vitro) Cervical cancer (HeLa, SiHa), (In vitro) Lung cancer | Inhibition of tumorigenesis, ↓Expression of proliferation markers, Enhancement of double-strand DNA break and apoptosis, Reduced therapy-induced organ toxicity | Jafri et al., 2010; Nessa et al., 2011; Al-Malki and Sayed, 2014; Hafiza and Latifah, 2014; Wilson et al., 2015 |
| Oxaliplatin (Oxptn) | Induction of DNA damage through Pt-mediated DNA crosslinking (Alkylating-like mechanism) | Counteracting drug resistance mechanisms | (In vitro) Osteosarcoma (MG63), (In vitro) Ovarian cancer, Pancreatic cancer | Reduced resistance to Oxptn and 5-FU and improvd cytotoxic effects at subtherpaeutic doses, Prevention of chemotherapy-induced toxicity and side effects | Banerjee et al., 2009; Nessa et al., 2011; Sarman et al., 2016 |
| Tamoxifen (TAM) | Anti-estrogens (compete with estrogen to bind with estrogen receptor) | XIAP-mediated Akt regulation | (In vitro) Breast Cancer (MCF-7, MDA-MB-231) | Synergistic cytotoxic effect through apoptosis induction | Rajput et al., 2013; Ganji-Harsini et al., 2016 |
| 5-Fluorouracil (5-FU) | Antimetabolites (inhibition of DNA replication and S-phase arrest) | Repression of procancerous signaling proteins (e.g. Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF) Upregulation of anti-tumorigenic proteins (e.g. DKK-1, CDNK-1A, TGF-β1, Smad4, and GPx) | (In vivo) Azoxymethane-induced colorectal tumorigenesis in male Wister rats, (In vitro) Gastric cancer | Chemosensitization of 5-FU, Attenuation of tumorigenesis | Lei et al., 2012; Kensara et al., 2016 |
| Gemcitabine (Gem) | Antimetabolites (nucleoside analogs) | Inhibition of NF-κB activation and Akt/mTOR/S6 signaling pathways, ↓ anti-apoptotic proteins, ↓ pro-apoptotic molecules Alteration in cancer cell metabolism by targeting pyruvate kinase M2 | (in vitro and in vivo) Pancreatic cancer / (PANC-1, MIA PaCa-2) | Chemosensitization of Gem (Synergistic induction of apoptosis and tumor growth inhibition) | Banerjee et al., 2009; Mu et al., 2015 |
| Topotecan (TP) | Topoisomerase-I inhibitor | Increased induction DNA damage and cell cycle arrest, ↓ Expression of anti-apoptotic proteins (e.g. Bcl2), ↑ Level of pro-apoptotic proteins (e.g. Bax, Caspase-3, Caspase-9) | (In vitro) Colorectal cancer, (In vitro) Acute myelogenous leukemia (U937) | Significant chemopotentiation of TP (antitumor activity at non-cytotoxic dose), Increased synergistic cytotoxic effects at non-cytotoxic dose of TP | Khalife et al., 2014, 2016 |
| Paclitaxel (Pac) | Interfere in mitotic spindle formation through stabilization of microtubule assembly | Upregulation of tumor suppressor genes (e.g. p21, Brca1) and pro-apoptotic proteins (cleaved caspase-3 and PARP), reduction of phosphorylated p65 and Atk1 | (In vitro) Tripple-negative Breast cancer | Synergistic inhibition of cancer cell growth along with increased cytotoxicity | Sakalar et al., 2016 |
| Docetaxel | Microtubule disrupting agent | PI3K and ERK signaling pathways | (In vitro) Castrate-resistant prostate cancer (CRPC)/DU-145 | Synergistic cytotoxicity and apoptosis | Dirican et al., 2015 |
| Doxorubicin (Dox) | Anti-tumor antibiotics | Selective killing of leukemia cells, Chemo-protective effects in normal cells, Upregulation of tumor suppressor proteins (e.g. PTEN) | (In vitro) Acute lymphoblastic leukemia, (In vitro) Breast cancer, (In vitro) Melanoma, (In vitro) Colon cancer, (In vitro) Cervical cancer | Improved anticancer activity of Dox (↑growth inhibition and apoptosis), Less organ toxicity | Arafa el et al., 2011; Effenberger-Neidnicht and Schobert, 2011; Brown et al., 2014 |
| Bortezomib | Proteosome inhibitor | Inhibition of NF-κB activation, ↓level of survival and angiogenic factors, Suppression of STAT3 activation | (In vitro) Multiple myeloma | Enhancement of overall anticancer activity (inhibition of cellular proliferation and induction of apoptosis) | Li et al., 2010; Siveen et al., 2014 |
| miR-34a | microRNA | Targets various epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) including twist-related protein 1 (TWIST1), SLUG, and NOTCH1 | (In vivo) Human metastatic breast cancer cells | Co-delivery of TQ and miR-34a resulted in synergistic inhibition of metastatic signaling pathways | Imani et al., 2017 |