Table 1.
Results of regorafenib-based combined treatments in preclinical HCC, CRC and GISTs models
| Cancer type | Model | Regorafenib-combined treatment schedule | Global effects | Molecular effects | Reference |
|---|---|---|---|---|---|
| HCC | HepG2, Hep3B, and Huh7 cell lines | Perifosine, MK2206 or PX-866 | Enhanced cell death | – | 32 |
| Sorafenib-resistant HepG2 xenografts | Anti-ANXA3 monoclonal antibody |
Tumor growth suppression Apoptosis induction Reduced autophagosome formation Inhibition of pro-survival autophagy |
↓ ANXA3 and LC3-II | 33 | |
| Genetically engineered immune-competent sorafenib non-responsive HCC mouse model | |||||
| HepG2 and Hep3B cell lines | Navitoclax (ABT-263) | Promotion of mitochondrial caspase-cell death |
↓ Mcl-1 ↑ Bim, caspase 3 activity, cytochrome c release, PARP cleavage |
34 | |
| PLC/PRF/5, HLF and HepG2 cell lines | VK1 plus GSK1838705A or OSI-906 |
Enhanced anti-proliferative and pro-apoptotic effects of regorafenib Cell migration impairment via actin depolymerization |
↓ AFP secretion (PLC/PRF/5 and HepG2) ↑ caspase 3/7 activation Loss of cytoplasm F-actin fibers but redistribution around de nucleus (HLF) ↓ p-ERK, p-AKT, p-p38, p-JNK, p-TSC2, p-S6 (PLC/PRF/5) |
35 | |
| HCC-PDX with high gankyrin levels | 2-DG, BPTES or 10058-F4 | Tumor growth repression | – | 36 | |
| PLC/PRF/5 cells | OA | Inhibition of cell growth, migration and invasion | – | 37 | |
| PLC-bearing mice | Reduction of tumor volume, lung metastasis, EMT, migration and invasion |
↑ E-cadherin ↓ Vimentin, MMP-2, MMP-9 |
|||
| PLC/PRF/5 and HepG2 cell lines | CGA |
Decreased cell proliferation and cell cycle progression from S to G2/M phase Apoptosis promotion Cell migration inhibition |
↓ Ki-67 ↑ Annexin V, Bax, caspase 3/7 activation ↓ Bcl-2, Bcl-xL ↓ p-JNK, p-p38, p-S6, p-TSC2, p-ERK, p-AKT |
38 | |
| HepG2 and Hep3B cells | CDDP | Synergistical inhibition of cell growth | – | 28 | |
| MHCC97H cells | Metformin |
Reduction of cell proliferation EMT suppression Apoptosis induction |
↓ HIF-2α, N-cadherin ↑ TIP30, E-cadherin |
39 | |
| Orthotopic MHCC97H mouse model |
Inhibition of postoperative recurrence and lung metastasis Apoptosis induction |
↓ Ki-67, N-cadherin ↑ TUNEL positive cells ↑ TIP30, E-cadherin |
|||
| CRC | COLO205, HT29, LoVo, HCT15 cells | Pimasertib | Synergistic effects on growth inhibition | – | 61 |
| HCT15 cells | Apoptosis induction |
↓ p-MAPK, p-AKT, p-4E-BP1, p-p70S6K, cyclin D1 ↑ p27 ↑ cleaved caspase 3, PARP |
|||
| SW620, SW480, HT29, and HCT116 cell lines | PX-866 | Enhanced cell death | – | 32 | |
| HCT116 cells | MK2206 | ||||
| HCT116 mouse model | MK2206 | Suppression of tumor growth | – | ||
| HCT116, SW480, HT29, and HCT116 p53−/− cells | 5-FU | Reduced cell viability |
↓ Mcl-1, Bcl-xL ↑ PUMA (HCT116 p53−/−) |
48 | |
| 5-FU resistant HCT116 (HCT116R) and DLD-1 (DLD-1R) cells | 5-FU |
Overcoming of 5-FU resistance Decrease of cell viability and tumor spheres formation |
– | 58 | |
| DLD-1R mouse model | Inhibition of tumor growth and tumor spheres formation |
↓ ABCG2, β-catenin, WNT1 ↑ Bax |
|||
| Oxaliplatin-refractory CRC-PDX | Irinotecan | Tumor growth delay | – | 50 | |
| HCT116 cells | 5-FU, oxaliplatin or cetuximab | Increased percentage of apoptotic cells | ↑ PUMA | 56 | |
| Mice with HCT116 xenograft tumors | 5-FU | Tumor volume decrease and apoptosis activation | ↑ TUNEL positive cells, active caspase 3 | ||
| HT29, SW620, LoVo, HCT15, SW48, SW480, HCT116, GEO and cetuximab-resistant GEO (GEO-CR), and SW48 (SW48-CR) cells | Cetuximab | Enhanced growth inhibition and apoptotic cells percentage (HT29, SW480, SW620, HCT116, LoVo, HCT15, SW48-CR, GEO-CR) | ↓ p-AKT, p-S6, p-MAPK (SW480, SW620, SW48-CR, GEO-CR, HCT116, LoVo, HCT15) | 51 | |
| Subcutaneous HCT15, HCT116, GEO-CR, and SW48-CR xenograft mouse models | Greater tumor volume reduction | – | |||
| Orthotopic HCT116 xenograft mouse model |
Inhibition of tumor growth in the cecum and metastasis formation Suppression of neovascularization |
– | |||
| SW620, HCT116, and HT29 cell lines | FTD | Inhibition of FTD incorporation into DNA |
↓ p-ERK ↓ TS |
62 | |
| FTD → regorafenib |
Higher survival inhibition Lower FTD incorporation into DNA Apoptosis induction (SW620) |
↑ cleaved PARP (SW620) ↓ p-ERK, TS |
|||
| SW620 and COLO205 xenograft mouse models | FTD/TPI → regorafenib | Higher inhibition of tumor growth | – | ||
| HCT116, HCT116 p53−/−, RKO and HT29 cells | CRT0066101 |
Cell growth inhibition Clonogenic growth inhibition (HCT116 and RKO) Apoptosis induction (RKO) |
↑ cleaved PARP (RKO) ↓ p-HSP27 (RKO) ↓ p-PKD2, p-AKT, p-ERK (RKO) ↓ p-PKD2 (HCT116) ↓ NF-κB activity (HCT116 and RKO) |
63 | |
| Mitoxantrone-resistant BCRP-overexpressing S1-M1-80 cells | Mitoxantrone or SN-38 |
Reversion of BCRP-mediated MDR Improvement of cells sensitivity to mitoxantrone or SN-38 Raised [3H]-mitoxantrone cellular retention via BCRP efflux impairment |
Interaction with the BCRP transmembrane domain | 64 | |
| Mitoxantrone-resistant BCRP-overexpressing S1-M1-80 xenografts | Topotecan | Reduced tumor volume and weight | – | ||
| Doxorubicin-resistant ABCB1-overexpressing SW620 cells (SW620/Ad300) | Paclitaxel |
Overcoming of ABCB1-mediated MDR Increased [3H]-paclitaxel cellular accumulation via ABCB1 efflux impairment |
↓ ABCB1 ATPase activity Interaction with the ABCB1 transmembrane domain |
65 | |
| SW620/Ad300 xenograft mouse model |
Synergistic effect on tumor growth inhibition Higher intratumoral paclitaxel concentration Increased plasma regorafenib concentration |
– | |||
| SW620/Ad300 cells | Paclitaxel, doxorubicin or vincristine |
Overcoming of ABCB1-mediated MDR Reduced resistance fold |
|||
| HCT116 and SW620 cell lines | Lapatinib |
Decreased survival rate Cell cycle arrest in G0/G1 phase (↑ G0/G1 phase cells and ↓ G2/M phase cells) (HCT116) Apoptosis induction |
↓ cyclins A, B, D1, E, CDK1, CDK6 ↓ p-AKT, p-ERK, Bcl-2, Mcl-1, XIAP, survivin ↑ cleaved PARP, Bax |
52 | |
| Subcutaneous HCT116 xenograft mouse model |
Tumor growth inhibition Diminished tumor volume and weight Inhibition of cell growth and angiogenesis |
↓ Ki-67, p-AKT, CD34 ↑ cleaved caspase 3, Bax |
|||
|
HCT116 and HT29 human cells CT26 and MCC38 mouse cells |
Sildenafil and neratinib |
Elevated cell death Increased toxic autophagosome formation (HCT116 and CT26) Activation of death receptor signaling (HCT116 and CT26) Lysosomal disfunction and release of cathepsin B (HCT116 and CT26) Mitochondrial disfunction and release of AIF (HCT116 and CT26) Modulation of tumor cells immunogenicity via autophagy-dependent regulation of HDAC proteins (CT26 and MCC38) |
↑ p-eIF2α, p-ATM, p-AMPK, p-ULK-1, p-S317, p-ATG13 (HCT116 and CT26) ↓ p-mTOR, p-AKT, p-p70S6K, p-ERK (HCT116 and CT26) ↑ ATG5, Beclin 1 (HCT116 and CT26) ↓ Mcl-1, Bcl-xL (HCT116 and CT26) ↓ p-GSK3, β-catenin (HCT116 and CT26) ↑ Frizzled (HCT116 and CT26) ↑ CD95 plasma membrane levels (CT26) ↓ HDAC proteins (CT26) ↓ PD-L1, IDO-1 (CT26 and MCC38) ↓ PD-L2 (CT26) ↑ MHCA (CT26 and MCC38) |
66 | |
| Mouse CT26 tumors | Enhanced reduction of tumor growth | – | |||
| D5D-knocking down HCA-7 colony 29 and HT29 cells | DGLA | Improvement of regorafenib inhibitory effect on cell viability and colony formation | – | 67 | |
| SW620, SW480, HCT15, HCT116, LoVo, SW48, GEO, SW48-CR, and GEO-CR | Silybin | Further cell growth suppression | – | 68 | |
| HCT15, SW480, SW48 and SW48-CR |
Reduced colony formation Higher ROS generation Apoptosis induction |
↑ cleaved PARP ↑ caspase 3, pro-caspase 9 (SW48, SW48-CR and HCT15) ↓ p-AKT, p70S6K, p-4E-BP1 |
|||
| EpCAM-positive HCT8 xenograft mouse model | CAR-modified NK-92 cells with specificity against EpCAM |
Lower tumor volume and weight Increased persistence of NK cells in the tumor |
– | 69 | |
| GISTs | Imatinib-resistant GIST430-654 cells | TL32711 or LCL161 | Increased pro-apoptotic activity |
↓ p-KIT, p-AKT, cIAP1, XIAP, survivin ↑ cleaved PARP |
78 |
4E-BP1 eukaryotic initiation factor 4E binding protein 1, 5-FU 5-fluorouracil, ABCB1 multidrug resistance protein 1, ABCG2 (BCRP) ATP-binding cassette sub-family G member 2, AFP alpha-fetoprotein, AIF apoptosis inducing factor, AKT protein kinase B, AMPK AMP‐dependent protein kinase, ANXA3 Annexin A3, ATG5 autophagy related protein 5, ATG13 autophagy related protein 13, Bax Bcl-2 associated X, Bcl-xL Bcl-2-like protein 1, Bim Bcl-2-like protein 11, CAR chimeric antigen receptor, CD34 hematopoietic progenitor cell antigen CD34, CD95 FAS cell surface death receptor, CDK1 cyclin-dependent kinase 1, CDK6 cyclin-dependent kinase 6, CGA chlorogenic acid, cIAP1 cellular inhibitor of apoptosis protein 1, CRC colorectal cancer, D5D delta-5-desaturase, DGLA dihomo-γ-linolenic acid, eIF2α eukaryotic translation initiation factor 2α, EMT epithelial-to-mesenchymal transition, EpCAM epithelial cell adhesion molecule, ERK extracellular signal-regulated kinase, FTD trifluridine, GISTs gastrointestinal stromal tumors, GSK3 glycogen synthase kinase 3, HCC hepatocellular carcinoma, HDAC histone deacetylase, HIF-2α hypoxia-inducible factor 2α, HSP27 heat shock protein beta-1, IDO-1 indoleamine‐pyrrole 2,3‐dioxygenase, JNK c-Jun N-terminal kinase, Ki-67 proliferation marker protein Ki-67, LC3-II microtubule-associated protein 1 light chain 3 II, MAPK mitogen-activated protein kinase, Mcl-1 induced myeloid leukemia cell differentiation protein, MDR multidrug resistance, MHCA major histocompatibility complex A, MMP-2 matrix metalloproteinase-2, MMP-9 matrix metalloproteinase-9, mTOR mammalian target of rapamycin, NF-ĸB nuclear factor-ĸB, NK natural killer, OA oleanolic acid, p phospho, p38 p38 MAPK, p70S6K ribosomal protein S6 kinase, PARP poly(ADP-ribose) polymerase, PD-L1 programmed cell death-1 ligand 1, PD-L2 programmed cell death-1 ligand 2, PDX patient-derived xenograft, PKD2 protein kinase D2, PUMA p53-upregulated modulator of apoptosis, ROS reactive oxygen species, S6 S6 ribosomal protein, TIP30 30 kDa HIV Tat-interacting protein, TPI tipiracil, TS thymidylate synthase, TSC2 tuberin, TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling, ULK-1 unc-51 like autophagy activating kinase 1, VK1 vitamin K1, WNT1 Wnt family member 1, XIAP X-linked inhibitor of apoptosis