Latest research on Velcade

Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

Velcade indications

As shown in Fig. 5C, the percentage of apoptotic and necrotic cells with PS-341 treatment was much lower in HepG2 and MDA-MB-453 cells with siRNA-mediated eIF2α silence than those without; and consistently the pro-apoptotic effects of the inhibition of these PS-341-induced miRs in PS-341-treated cells were also abolished by eIF2α knockdown (Fig. 5C).Concomitant overexpression of an eIF2α (eIF2α-ORF) that is resistant to miR-30b-5p and miR-30c-5p in both HepG2 and MDA-MB-453 cells robustly abrogated the anti-apoptotic effect of overexpression of miR-30b-5p or miR-30c-5p (Supplementary Fig. 2). [source, 2016]
Consistent with these previous reports, our present study reveals that, miR-30b-5p, miR-30c-5p, miR-664–3p, miR-106–5p, miR-182–5p and miR-193–3p are induced by PS-341, demonstrates that at least miR-30b-5p and miR-30c-5p can serve as tumor facilitators which elevate cell viability and anti-apoptosis capacity, and shows that using the specific inhibitor of these miRs along with a proteasome inhibitor can lead to more effective apoptosis induction and better anti-tumor effects than using proteasome inhibitor alone. [source, 2016]
Velcade (bortezomib) was the first clinically approved UPS inhibitor and is used as a therapeutic agent for B cell lymphoma and multiple myeloma, exemplifying the importance of the UPS as an effective therapeutic target (Bold 2004). [source, 2015]
Varying treatment regimens between countries, as well as changes in treatment guidelines leading to the use of a product for new indications or new patient groups in one country over time, may influence the reporting of a lack of effect for this type of drug, compared with the background rate, and hence could explain the unexpectedly high reporting rate for Velcade in the UK. [source, 2015]
Since receptor overexpression, such as EGFR, can result in sustained activation of downstream signaling [20], and we previously reported that the ubiquitin ligase inhibitor PS-341 enhances RANK expression in MDA-MB-231 cells, we examined the effect of Cbl-b on RANK expression. [source, 2015]
To elucidate possible approaches to specifically inhibit the proteasome to suppress MBP proteolysis, we analyzed the effect of 3 inhibitors of proteolytic activity on isolated CP and IP in vitro: PS-341 (which affects all catalytic subunits of the CP and the IP), MG132 (an inhibitor of chymotrypsin-like activity), and a specific inhibitor of the β1i subunit, peptidyl epoxyketone (PEk), which irreversibly binds to the Threonine in the active center of the β1i subunit. [source, 2015]
PS-341 and MG132 showed similar effects that were not influenced by the CP/IP ratio, whereas proteasomes from EAE-SJL mice were significantly more inhibited by β1i-PEk than CPs purified from the brains of BALB/c mice (Fig. 6). [source, 2015]
Because the majority of cancer cells exhibit higher levels of proteasome activity, they are more prone to the negative effects of proteasome inhibitors such as bortezomib (BTZ, Velcade), a reversible proteasome inhibitor that has been approved by the FDA to treat subtypes of hematological malignancies including plasma cell myeloma and mantle cell lymphoma [24, 27]. [source, 2015]
In the context reviewed here, bortecimib can have serious side effects on the nervous system (see Velcade EMA/27714/2015) such as posterior reversible encephalopathy syndrome, autonomic neuropathy (damage to nerves controlling organs such as the bladder, eyes, gut, heart, and blood vessels), or more commonly peripheral neuropathy (nerve damage in hands and feet). [source, 2015]
We believe that HKH40A can be particularly effective when combined with established anticancer drugs known to upregulate BiP that usually run into problems of chemoresistance (eg, Gemcitabine (Gemzar) or Velcade). [source, 2014]