CN-121265571-B - Application of cryptoxanthin in preparation of drug-resistant multiple myeloma combined drug for treating lenalidomide

CN121265571BCN 121265571 BCN121265571 BCN 121265571BCN-121265571-B

Abstract

The invention discloses application of cryptoxanthin in preparation of a drug-resistant multiple myeloma combined drug for treating lenalidomide, and relates to the technical field of medicines. The invention verifies the effect and potential mechanism of beta CRY in treating LEN drug-resistant MM through in vivo and in vitro experiments, specifically, the beta CRY can induce iron death through inhibiting the expression level of FSP1 protein in LEN drug-resistant tumor, thereby remarkably reducing the activity of LEN drug-resistant tumor cells and finally achieving the aim of overcoming LEN tumor drug resistance. The discovery in the invention proves that a plant extract is used as a novel FSP1 inhibitor to treat LEN-resistant MM cells, and provides a theoretical basis for further treating LEN-resistant MM by using beta CRY clinically. Therefore, the invention has better application prospect in the field of treating drug-resistant MM.

Inventors

HUANG HONGMING
ZHANG TINGTING
GUO DAN
XU JINTAO
GAO ZITING

Assignees

南通大学附属医院

Dates

Publication Date: 20260512
Application Date: 20251203

Claims (6)

1. Use of cryptoxanthin in the manufacture of a medicament for the treatment of multiple myeloma, wherein the multiple myeloma comprises lenalidomide resistant multiple myeloma.
2. Use of a pharmaceutical composition comprising cryptoxanthin in the manufacture of a medicament for the prevention and treatment of multiple myeloma, wherein the multiple myeloma comprises lenalidomide resistant multiple myeloma.
3. The use according to any one of claims 1-2, wherein the medicament is in the form of any one of a capsule, a tablet or an injection.
4. The use according to claim 3, wherein the medicament is administered by injection or orally.
5. The use of claim 4, wherein the medicament inhibits lenalidomide resistant multiple myeloma by activating the iron death pathway.
6. The use according to claim 5, wherein the medicament induces iron death by inhibiting the expression level of FSP1 protein in lenalidomide resistant tumor cells, thereby reducing the activity of lenalidomide resistant tumor cells and finally overcoming lenalidomide tumor resistance.

Description

Application of cryptoxanthin in preparation of drug-resistant multiple myeloma combined drug for treating lenalidomide Technical Field The invention belongs to the technical field of medicines, and particularly relates to application of a plant extract cryptoxanthin in preparation of a medicine for preventing and treating lenalidomide drug-resistant multiple myeloma. The invention obviously inhibits the activity of drug-resistant myeloma cells by activating an iron death way, and provides a new drug choice for clinically treating drug-resistant multiple myeloma. Background Multiple Myeloma (MM) is a malignant hematological tumor that originates from plasma cells and is characterized by abnormal proliferation of clonal plasma cells in the bone marrow and secretion of large amounts of monoclonal immunoglobulins (M protein). MM is the second most common hematologic malignancy, accounting for about 1% of all cancers, which has a significant propensity for bone destruction, leading to osteolytic lesions, primarily through activation of osteoclasts and inhibition of osteoblast activity, and is clinically manifested as bone pain, pathological fractures, and hypercalcemia. In addition, MM can also cause complications such as impairment of renal function (common light chain tubular kidney disease), anemia (due to bone marrow infiltration and erythropoietin depletion), recurrent infections resulting from immune dysfunction. Although recent advances in therapeutic approaches, including combination therapies of proteasome inhibitors (e.g., bortezomib), immunomodulatory drugs (e.g., lenalidomide/thalidomide), monoclonal antibodies (e.g., CD38 mab-Lei Tuoyou mab), and autologous hematopoietic stem cell transplantation have significantly improved patient prognosis, the vast majority of patients eventually relapse due to acquired drug resistance. As an immunomodulatory drug, almost all MM patients are exposed to Lenalidomide (LEN), and although LEN has potent anti-MM activity, some patients eventually relapse and develop LEN resistance. Drug resistance is one of the biggest challenges facing modern oncology and has become the primary cause of cancer treatment failure. The number of patients receiving LEN is increasing, and therefore the problem of LEN resistance has become a major obstacle for blood scientists worldwide. At present, the disease is still considered incurable, and the survival rate of 5 years is only 50%, so that the exploration of new therapeutic targets and the development of new therapeutic strategies have important clinical significance. Cryptoxanthin (beta-cryptoxanthin, beta CRY) is an oxygen-containing carotenoid, and has a chemical structure of 3-hydroxy-beta-carotene, and is mainly found in citrus fruits (such as orange and grapefruit), persimmon, corn, capsicum, etc. in nature. As provitamin a, it can be converted into retinaldehyde in human body by central cleavage, and further participates in physiological processes such as visual circulation, epithelial cell differentiation and immunomodulation. In recent years, researches show that cryptoxanthin has wide pharmacological activity, namely ① antioxidation, namely relieving oxidative stress injury by scavenging free radicals and activating Nrf2/ARE channels, ② anti-inflammatory, namely inhibiting NF- κB and MAPK signal channels, ③ bone protection, namely promoting osteoblast differentiation and inhibiting osteoclast generation, ④ is particularly important as anticancer activity, and has been proved to play an anti-tumor effect by regulating and controlling cell cycle, inducing apoptosis, inhibiting metastasis and other mechanisms in various tumor models such as liver cancer, colon cancer, breast cancer and the like. However, the role of cryptoxanthin in hematological malignancies, particularly drug-resistant multiple myeloma, and its molecular mechanism have not been systematically studied. Iron death (Ferroptosis) is characterized in its core by the abnormal accumulation of iron-dependent lipid peroxides (lipid ROS) leading to oxidative damage of the cell membrane system. Unlike traditional apoptosis, iron death is morphologically represented by unique changes such as mitochondrial cristae reduction/disappearance, mitochondrial membrane shrinkage, membrane density increase, and is not affected by caspase inhibitors. The molecular mechanism mainly relates to ① glutathione metabolism disorder, reduction of cystine intake caused by inhibition of a system Xc-transporter, further consumption of Glutathione (GSH), inhibition of GPX4 activity of ② key antioxidant enzyme, direct or indirect phospholipid hydroperoxide removal disorder, ③ iron metabolism disorder, and catalysis of ROS generation by free iron through Fenton reaction. Research shows that iron death has unique therapeutic value in the tumor field, and many tumor cells resistant to traditional treatment (such as cisplatin-resistant ovarian cancer cells and EGFR-TKI-resistant lung cancer cells)