Table 1.
The effects of HO-1-contributed resistance to chemotherapeutic agents and radiation therapy.
| Therapeutic Treatment | Cancer Types | HO-1 Status | Resolution or HO-1 Regulator | Reference |
|---|---|---|---|---|
| BIX-01204 (G9a inhibitor) | KG leukemia stem cells | Induced PERK–autophagy–ROS–HO-1 | PERK inhibition (shRNA, GSK2606414) or autophagy inhibition (Bafilomycin A1) to inhibit Nrf2/HO-1 and increase ROS | [127] |
| Bortezomib (BTZ) | Neuroblastoma: HTLA-231 and MDA | Increased Nrf2 and HO-1 | ZnPP co-treatment enhanced sensitivity of BTZ-mediated apoptosis | [128] |
| Bortezomib (BTZ) | Neuroblastoma: HTLA-230 | Activated Nrf2 to increase HO-1 gCLM, xCT, and GSH | HO-1 siRNS sensitized BTZ-induced cell death, all-trans retinoic acid (Nrf2 inhibitor) reversed BTZ-increased HO-1, gCLM, xCT, and GSH, and sensitized Bortezomib-induced cytotoxicity | [129] |
| Bortezomib (BTZ) | Multiple myeloma (U266, KMS26 SKM-M1, and MM1S) |
Induced ER stress, ROS generation, and upregulated nuclear HO-1 | E64d prevented nuclear localization of HO-1 and increased BTZ sensitivity | [78] |
| Bortezomib (BTZ) | Parent U226 and bortezomib-resistant U266 | Theioredoxin reductase regulated Nrf2 and HO-1 | ZnPP restored BTZ-mediated apoptosis | [130] |
| Cisplatin | Ovarian cancer: SKOV-3 and CAOV-3 Human ovarian cancer tissues |
Induced Sirtuin 5–Nrf2–HO1 pathway to inhibit ROS generation Higher Sirtuin-5 expression |
Sirtuin 5 siRNA sensitized cisplatin-induced ROS and DNA damage | [126] |
| Cisplatin | Hepatoma cells: HepG2, 97H, and SMMC7721 HepG2 xenograft |
Increased HO-1 expression | ZnPP co-treatment increased ROS, caspase-3 activity, and apoptosis ZnPP enhanced cisplatin-inhibited tumor growth |
[131] |
| Cisplatin and pisrarubicin | Hepatoblastoma: HepG2 Human hepatoblastoma specimens (cisplatin and pirarubicin) |
Induced EGFR–AKT/ERK–HO-1 | EGFR inhibitor (AG1478) and siHO-1 sensitized cisplatin and pirarubicin-induced cell death | [132] |
| Cytarabine | Leukemia HL-60 and cytarabine-resistant HL-60 (HL-60R) Chemotherapy relapsed samples |
HL-60R cells have higher HO-1 expression compared to parental HL-60 Higher HO-1 and HIF-α expression |
HO-1 siRNA sensitized cytarabine-induced apoptosis in HL-60R cells | [133] |
| Doxorubicin (DOX) | Breast cancer: MDA-MB-231, and -MB-231 | Induced Src–STAT3–HO-1 Increased HO-1 induced a cytoprotective autophagic flux and increased both Beclin-1 and LC3-I/II |
SiRNA of Src and STAT3 sensitized DOX-induced cell death and DOX-increased HO-1, and prevented HO-1-upregulated Beclin-1 and LC3-I/II | [121] |
| Doxorubicin Vinblastine Radiation |
Lung adenocarcinoma cells: A549 | HRP-3–Nrf2–HO-1–ROS–p53–PUMA pathway mediated chemoresistance and radioresistance | HRP3 siRNA enhanced sensitivity of doxorubicin, vinblastine, and radiation-induced apoptosis | [134] |
| 5-Fluoracil (5-FU) | MDR1-overexpressed colon carcinoma (HCT-116/R) | HCT-116/R cells expressed higher expression of HIF-1F, Nrf2, and HO-1, as well as increased NOX2 activity and ROS compared to parental cells | NOX inhibitor (HDC) and Nrf2 inhibitor (ML-385) enhanced 5-FU-induced apoptosis | [135] |
| 5-Fluorouracil (5-FU) | Pancreatic cancer, CPFAC and BxPC-3 | Increased HO-1 (higher NQO1 and SOD2) Higher EMT marker (Nanog, Oct4, CD133, and ABCG2) |
Nrf2 siRNA increased sensitivity of 5-FU-mediated cytotoxicity | [136] |
| 5-Fluorouracil (5-FU) | Colorectal cancer: SNUC5 and 5-FU-resistant SUNC5 (SNUC5-5-FUR) | ISNUC5-5-FUR exhibited increased ROS–Nrf2–HO-1 compared to parental cells | shRNA of Nrf2 or HO-1 enhanced sensitivity of 5-FU-mediated apoptosis of SNUC5-5-FUR cells and tumor inhibition in SNUC5-5-FUR xenograft mouse | [137] |
| Gemcitabine Radiation |
Pancreatic cancer cells: Panc-1, Mla PaCa-2, SU8686, and Colo 357 | Increased HO-1 expression | HO-1 siRNA enhanced sensitivity to Gemcitabine and radiation-mediated cell death | [119] |
| Gemcitabine Radiation |
Urothelial carcinoma: T24 and MGHU3 | Increased HO-1 expression | ZnPP co-treatment enhanced sensitivity of gemcitabine or radiation-mediated apoptosis | [120] |
| NMS E793 | A375 melanoma cells | Upregulated ER stress response protein IRE1α, ERO-1, GRP78, and CHOP Upregulated HO-1 |
SnMP (HO-1 inhibitor) co-treatment induced higher ER stress, increased ROS, and promoted apoptosis | [138] |
| Pharmorubicin | MDA-MB-231, MCF-7 breast cancer cells | Induced PI3K-AKT-HO-1-autophpagy (LC3-I/II) | HO-1 siRNA sensitized pharmorubicin-mediated reduced chemoresistance | [124] |
| Radiation | Lung adenocarcinoma cells: A549 | Increased HO-1 and ROS levels | HRP-3 knockdown Inhibited Nrf2/HO-1 Enhanced ROS |
[134] |
| Low-dose radiation | Lung adenocarcinoma cells: A549 | Induced ROS–autophagy–Nrf2-HO-1 | NAC (ROS scavenger) blocked autophagy and Nrf2/HO-1; Nrf2 knockdown or ZnPP treatment reversed resistance to radiation |
[125] |