Selective inhibitors of nuclear export (SINEs or SINE compounds) are drugs that block

exportin 1 Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs. History XPO1 (CRM1) originally was identified in the fission yeast ''Schizosaccharom ...

(XPO1 or CRM1), a protein involved in transport from the

cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...

to the cytoplasm. This causes cell cycle arrest and cell death by

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. Thus, SINE compounds are of interest as

anticancer drugs Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

; several are in development, and one ( selinexor) has been approved for treatment of

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

as a drug of last resort. The prototypical nuclear export inhibitor is leptomycin B, a

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

and secondary metabolite of ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

'' bacteria. Although it is nonselective and too toxic for clinical use in humans, the discovery of its mechanism of action and antitumor properties prompted development of the SINE compounds.

Mechanism of action

SINEs work by binding to CRM1, a karyopherin which performs nuclear transport of hundreds of proteins—including tumor suppressors, oncogenes, and proteins involved in governing cell growth—from the

to the cytoplasm. CRM1 it is often overexpressed and misregulated in cancer, and is the sole transporter of many proteins essential for cancer cell proliferation and spread. By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell growth, ultimately triggering

. ''In vitro'', this effect appears to spare normal (non-malignant) cells. Nevertheless, because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which causes a high rate of adverse reactions.

Research

SINEs have been tested in several preclinical animal models of cancer, including

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...

, breast cancer, non-small-cell lung cancer, lymphomas, and acute and chronic leukemias. In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphoma,

blast crisis Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulati ...

, and a wide range of advanced or refractory solid tumors, including

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...

, head and neck cancer,

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

, ovarian cancer, and

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

Compassionate use Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life ...

in patients with acute myeloid leukemia has also been reported.

Mechanism of action

Research

References

Further reading