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Abstract
Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.
Highlights
Ovarian cancer (OC) is the deadliest gynecologic malignancy, responsible for over 50 percent of mortality among all gynecologic malignancies worldwide [1,2]
Twist expression gradually increased with increasing intermittent cisplatin doses at 10 to 100 μm which may contribute to the development of cisplatin resistance
In both cancer cell lines, Twist amplification coincided with an increased expression of DNA damage response (DDR) genes, including Poly (ADP-ribose) polymerase 1 (PARP1) and XRCC1 (Figure 1B and Figure S1)
Summary
Ovarian cancer (OC) is the deadliest gynecologic malignancy, responsible for over 50 percent of mortality among all gynecologic malignancies worldwide [1,2]. OC die from recurrent diseases and resistance to platinum-based chemotherapy. An alternative therapeutic strategy to treat patients with recurrent OC is urgently needed. Several novel strategies for potential personalized therapy have been established, including molecular-targeted medicine (small-molecule inhibitors or antibodies), clinical immunotherapeutic applications and the recognition of synthetic lethal partners [4]. Genetic screening techniques, including computer methods, drug screening, genetic modification with shRNA/siRNA or CRISPR, or a combination of these methods, can recognize synthetic lethal partners [5,6,7]. The alteration of the DNA damage response (DDR) pathway is a predictive biomarker of platinum-based sensitivity in various cancers, including OC [8]
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