Selinexor (Xpovio) is a targeted cancer therapy belonging to the Selective Inhibitor of Nuclear Export (SINE) class of compounds. It is approved for specific hematologic malignancies, including certain types of relapsed or refractory multiple myeloma (often in combination with dexamethasone or bortezomib and dexamethasone) and diffuse large B-cell lymphoma (DLBCL). This medication offers a novel mechanism for addressing these difficult-to-treat cancers, providing an important option for patients who have undergone previous therapies.
The Function of Exportin 1 in Cells
Keywords: “Exportin 1 normal function”, “XPO1 nuclear transport”, “protein shuttle nucleus cytoplasm”
To understand how selinexor works, consider the normal activities within a cell. The nucleus contains genetic instructions, while the cytoplasm is where proteins are produced and function. Efficient cell operation requires specific proteins and RNA molecules to move between these compartments.
This transport is managed by specialized proteins, primarily Exportin 1 (XPO1), also known as Chromosomal Maintenance 1 (CRM1). XPO1 is responsible for moving hundreds of different proteins and various RNA species from the nucleus to the cytoplasm. It recognizes specific nuclear export signals (NES) on its cargo molecules, ensuring only designated substances exit. This regulated movement is a fundamental cellular process, maintaining proper protein localization and healthy cell function, including growth, differentiation, and survival.
Nuclear Export in Cancer Cells
Keywords: “XPO1 overexpression cancer”, “tumor suppressor protein nuclear export cancer”, “XPO1 therapeutic target”
In many types of cancer, this cellular transport system becomes disrupted. Cancer cells frequently exhibit an overexpression of XPO1, meaning they produce excessive amounts of this export protein. This increased XPO1 activity creates an imbalance in nuclear-cytoplasmic transport. It actively shuttles important proteins, specifically tumor suppressor proteins, out of the nucleus and into the cytoplasm.
Tumor suppressor proteins are natural safeguards that normally reside in the nucleus, where they control cell growth and division. When these proteins are forcibly exported from the nucleus by overactive XPO1, they become trapped in the cytoplasm. Outside the nucleus, they cannot access the cell’s genetic material to perform their growth-regulating functions, thereby losing their ability to suppress abnormal cell proliferation. This mislocalization allows cancer cells to grow and divide uncontrollably, making XPO1 an attractive target for therapeutic intervention.
Selinexor’s Direct Action on XPO1
Keywords: “selinexor binds XPO1 mechanism”, “selinexor blocks XPO1 transport”
Selinexor is specifically designed to counteract the aberrant activity of XPO1 in cancer cells. This drug works by directly binding to the XPO1 protein. Selinexor forms a covalent bond with a particular amino acid, cysteine-528, located within XPO1’s cargo-binding pocket.
By binding to this site, selinexor effectively blocks XPO1’s transport function. This physical obstruction prevents XPO1 from recognizing and exporting its cargo, including tumor suppressor proteins, out of the nucleus. This direct, specific interaction is what defines selinexor as a Selective Inhibitor of Nuclear Export.
Restoring Tumor Suppression and Cell Death
Keywords: “selinexor tumor suppressor proteins accumulation nucleus”, “selinexor apoptosis cancer”, “p53 BRCA1 p21 nuclear accumulation selinexor”, “selinexor dexamethasone glucocorticoid receptor”
The inhibition of XPO1 by selinexor has significant consequences for cancer cells. With the nuclear export pathway blocked, tumor suppressor proteins, which were previously forced out, become trapped and accumulate inside the nucleus. This includes tumor suppressors such as p53, BRCA1, p21, and FOXO.
Their re-accumulation in the nucleus allows these proteins to resume their functions in controlling cell growth and integrity. Once nuclear levels of these proteins are restored, they can halt the cancer cell’s replication cycle, preventing uncontrolled division. The accumulation of these tumor suppressor proteins often triggers apoptosis, which is the cell’s own mechanism for programmed cell death. Selinexor also enhances the expression of glucocorticoid receptors (GR). When combined with steroids like dexamethasone, which activate GR, it synergistically increases anti-tumor activity and promotes cancer cell death, particularly in multiple myeloma.