Targeting CD146 in combination with vorinostat for the treatment of ovarian cancer cells

Abstract

Drug resistance is the predominant cause of mortality in late-stage patients with ovarian cancer. Histone deacetylase inhibitors (HDACis) have emerged as a novel type of second line drug with high specificity for tumor cells, including ovarian cancer cells. However, HDACis usually exhibit relatively low potencies when used as a single agent. The majority of current clinical trials are combination strategies. These strategies are more empirical than mechanism-based applications. Previously, it was reported that the adhesion molecule cluster of differentiation 146 (CD146) is significantly induced in HDACi-treated tumor cells. The present study additionally confirmed that the induction of CD146 is a common phenomenon in vorinostat-treated ovarian cancer cells. AA98, an anti-CD146 monoclonal antibody (mAb), was used to target CD146 function. Synergistic antitumoral effects between AA98 and vorinostat were examined in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the protein kinase B (Akt) pathway was determined by western blotting. The present study found that targeting of CD146 substantially enhanced vorinostat-induced killing via the suppression of activation of Akt pathways in ovarian cancer cells. AA98 in combination with vorinostat significantly inhibited cell proliferation and increased apoptosis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and prolong survival in ovarian cancer. These data suggest that an undesired induction of CD146 may serve as a protective response to offset the antitumor efficacy of vorinostat. By contrast, targeting CD146 in combination with vorinostat may be exploited as a novel strategy to more effectively kill ovarian cancer cells.

CD146, from a melanoma cell adhesion molecule to a signaling receptor

“…Under pathological conditions, such as inflammation and tumorigenesis, CD146 was upregulated in the related cells and has been identified as a reliable marker for numerous types of cancers. Accumulating evidence shows that CD146 overexpression has been linked to either the initial development of the primary lesion or progression to metastases of most of cancer types, primarily including melanoma, 1,27-29 breast, 6,30,31 ovarian, [32][33][34][35] lung, 36,37 prostate, [38][39][40] glioma, 41 kidney, 42 hepatic, 43,44 and gastric cancers. 21,45 In 2017, Nollet et al reported that TsCD146 mAb (for tumor specific anti-CD146 monoclonal antibody) can specifically recognize CD146 expressed in cancer cells but not CD146 in physiological vessels, suggesting that structural features of cancer CD146 differ from those of physiological CD146.…”

MicroRNA-132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF‑κB and VEGF pathway

“…Ischemic cerebrovascular disease (ICD) refers to a group of clinical syndromes arising from cerebral circulatory dysfunction of various causes, and brain damage and neurological dysfunction of patients caused by cerebral ischemia, hypoxia and necrosis at the associated blood vessel zone (1). The incidence rate of ICD among cerebrovascular diseases is ~70% in China (2).…”

“…According to the data of one survey, it possesses the highest disability and mortality rate in China (4). The incidence rate is rising at an annual growth rate of 8.7%, reflecting China's aging population (1).…”

Epigenetic Mechanisms in Canine Cancer

“…The first HDACi, SAHA (Vorinostat, Zolinza ™ , Merck & Co, Inc., USA), was approved by FDA in 2006, and since then, HDACi are being developed for the treatment of T-cell lymphoma (194)(195)(196) and multiple myeloma (197). Furthermore, other studies and clinical trials showed the effects of Vorinostat in hematological and solid cancers including pancreatic (198), ovarian (199), prostate (200), and breast cancer (201).…”