Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling
Abstract
:1. Introduction
2. IL-6/GP130 Signaling Pathway in Cancer
3. Bazedoxifene Is a Novel Inhibitor of IL-6/GP130 Signing
4. Effect of Bazedoxifene on Breast Cancer
5. Effect of Bazedoxifene in Other Types of Cancer
5.1. Colon Cancer
5.2. Ovarian Cancer
5.3. Other Cancer Types
6. Clinical Trials of BZA in Cancer
7. Limitation of BZA in Cancer
8. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Receptor Expression | Frequency, % | 5-Year Survival, % | Therapy | |
---|---|---|---|---|
Luminal A | ER+, PR+, HER2− | 50 | 94.8 | Hormonal |
Luminal B | ER+, PR+/−, HER2− | 15 | Hormonal/Chemo | |
Luminal/HER | HR+, HER2+ | 15 | 91.0 | Hormonal/Chemo |
HER enriched | HR−, HER2+ | 5 | 85.6 | Hormonal/Chemo |
TNBC | ER−, PR−, HER2− | 15 | 77.6 | Chemo/Experimental |
Cell Lines | Biological Effects | Molecular Target Inhibited | Reference |
---|---|---|---|
TNBC: MDA-MB-231, MDA-MB-468, SUM159 | (1) BZA alone inhibits cell viability, survival, proliferation, and cell migration in all TNBC cells. (2) Tumor growth in mice was remarkably suppressed by BZA via an oral administration route. | p-STAT3, p-ERT, and p-AKT ↓ | [10] |
ER+ breast cancer cells: MCF-7, T47D, MCF-7:5C, MCF-7:2A | (1) BZA inhibited the growth of both hormone-dependent and -independent ER-positive breast cancer cells. (2) BZA induced G1 blockade in hormone-independent MCF-7:5C cells. | ERα, cyclin D1 ↓ | [15] |
ER+ breast cancer cells: MCF-7, ZR75-1 T47D | (1) BZA is a potent inhibitor against somatic mutants of ERα (Y537S and D538G) in breast cancer cells. (2) BZA has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. | ERα, cyclin D1, c-myc, and PR ↓ | [46] |
ER+ breast cancer cells: MCF7, T47D, BT474. TNBCs: MDA-MB-231, MDA-MB-468, 4T1 | (1) BZA inhibited cell viability, clonal formation, migration, and induces apoptosis in both ER+ and TNBC cell lines. (2) BZA alone suppressed tumor growth in the TNBC xenograft model (3) BZA and paclitaxel combination exhibits more potent inhibition of the malignant features of breast cancer than either drug alone. | ER+ breast cancer cells: ERα ↓ TNBC: p-STAT3, p-ERT, and p-AKT ↓ | [47] |
Cancer Type and Reference | Cell Lines | Biological Effects | Molecular Target Inhibited |
---|---|---|---|
Rhabdomyosarcoma [48] | RH4, RH5, and RH30 | (1) BZA inhibited cell migration and induced apoptosis in rhabdomyosarcoma cells. (2) BZA enhanced the sensitivity of rhabdomyosarcoma cells to anticancer drugs such as doxorubicin, cisplatin, or AZD6244 by inhibiting GP130 signaling. | p-STAT3, cytochrome c ↓ |
Pancreatic cancer [49] | PANC-1, HPAF-II, Capan-1, BxPC-3, and MIA PaCa-2 | (1) BZA impeded IL-6 mediated cell viability, proliferation, glycolysis, and colony formation in pancreatic cancer cells. | IL-6R, p-STAT3, AKT1 ↓ |
Brain cancer [55] | Glioblastoma cells | (1) BZA inhibited glioblastoma cell viability in a dose-dependent manner. (2) When combined with paclitaxel, BZA more effectively suppressed glioblastoma progression by enhancing apoptosis and reducing EMT. | ERα, Cyclin D1, Bcl-2, p-p70S6K, vimentin, MMP9 and snail ↓ Cleaved caspase-3 ↑ |
Cervical Cancer [56] | HPV-positive cervical cancer cell lines: SiHa, HeLa and CaSki | (1) BZA reduced cell proliferation, colony formation, migration, and invasion while promoting apoptosis in HPV-positive cervical cancer cells. (2) BZA inhibited tumor growth in a dose-dependent manner in the SiHa mouse xenograft model and suppressed the progression of epithelial-mesenchymal transition (EMT). | Bcl-xL, Mcl-1, pGP130, pSTAT3 pERK1/2, β-catenin, vimentin, Wnt5β ↓ Bim, Bax, E-cadherin ↑ |
Colon cancer [57] | DLD-1, HCT-15, and HCT-116 | (1) BZA alone or combined with oxaliplatin can induce apoptosis and inhibit cell viability, cell colony formation, and cell migration in colon cancer cells. (2) BZA (10 mg/kg) alone attenuated HCT-15 xenograft tumor burden. | p-STAT3, p-AKT, Cyclin D1, survivin, c-myc ↓ |
Hepatocellular carcinoma [59] | Human liver cancer cell lines: Hep3B, HEPG2, SSMC 7721, HUH-7 | (1) BZA inhibited cell viability, wound healing, and colony formation while inducing apoptosis in liver cancer cells. (2) In a HEPG2 mouse xenograft model, BZA effectively suppressed tumor growth. | p-STAT3, p-JAK1, p-JAK2, Bcl-2, surviving ↓ Translocation of STAT3 ↓ Cleaved caspase-3 ↑ |
Ovarian cancer [75] | SKOV3, UWB1.289 (BRCA1-null) and OV75 | (1) BZA combined with PARP inhibitor talazoparib synergistically inhibits cell viability, cell migration, cell growth, and cell colony formation on all ovarian cell lines. | p-AKT, c-myc, p-ERK, ERα ↓ γ-H2AX ↑ |
Bone tumor [76] | Osteosarcoma cancer cell lines: SJSA, SaoS2, 143B | (1) BZA reduced cell viability and migration in osteosarcoma cells by inhibiting IL-6 and IL-11/GP130 signaling pathways. (2) When combined with temsirolimus, BZA synergistically suppressed osteosarcoma progression in both in vitro and in vivo models. | p-STAT3, p-ERK1/2, p-AKT, survivin ↓ Cleaved caspase-9 ↑ |
Title | Phase | Intervention | Cancer Type | Outcome |
---|---|---|---|---|
Bazedoxifene and conjugated estrogens for the prevention of breast cancer in peri- or postmenopausal women at increased risk for development of breast cancer | Phase II | BZA + conjugated estrogens | Breast Cancer Prevention | 1. a significant reduction in mammographic fibroglandular volume, serum progesterone, bioavailable testosterone, and IGF-1 levels, as well as an increase in bioavailable estradiol. 2. a reduction in Ki-67 levels for women in the higher-risk cohort 3. an improvement in hot flash symptoms and overall menopause-related quality of life. |
A phase Ib/II study of palbociclib in combination with bazedoxifene in hormone Receptor-positive breast cancer | Phase Ib/II | Palbociclib + BZA | Hormone Receptor-Positive (HR+) Breast Cancer | 1. Promising clinical efficacy in patients with advanced HR+ breast cancer, with some patients experiencing tumor shrinkage or disease stabilization. 2. The treatment regimen was generally well tolerated, with manageable side effects consistent with those typically seen in palbociclib therapy, such as neutropenia, fatigue, and gastrointestinal symptoms. |
A large-scale multicenter Phase II study evaluating the protective effect of a tissue-selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ | Phase II | BZA + conjugated estrogens | Ductal Carcinoma in Situ (non-invasive or pre-invasive breast cancer) | Ongoing, 1. investigated the proliferation of cancer cells (Ki-67) and expression of hormone receptors such as ERα, PR, and HER-2, along with other markers related to tumor progression. 2. examined the impact of CE/BZA on quality of life, assessing potential side effects and menopausal symptom relief. |
Bazedoxifene as a concomitant treatment of patients with metastatic pancreatic adenocarcinoma | Phase II | BZA + gemcitabine with or without nab-paclitaxel | Metastatic pancreatic adenocarcinoma with IL6/GP130/STAT3 pathway activity | Ongoing, 1. measures changes in the expression of the IL-6/GP130/STAT3 pathway and tumor markers (such as CA 19-9) 2. evaluate patient quality of life. 3. Toxicity and safety assessments. |
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Shi, C.; Bopp, T.; Lo, H.-W.; Tkaczuk, K.; Lin, J. Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling. Curr. Oncol. 2024, 31, 5737-5751. https://doi.org/10.3390/curroncol31100426
Shi C, Bopp T, Lo H-W, Tkaczuk K, Lin J. Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling. Current Oncology. 2024; 31(10):5737-5751. https://doi.org/10.3390/curroncol31100426
Chicago/Turabian StyleShi, Changyou, Taylor Bopp, Hui-Wen Lo, Katherine Tkaczuk, and Jiayuh Lin. 2024. "Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling" Current Oncology 31, no. 10: 5737-5751. https://doi.org/10.3390/curroncol31100426