Ovarian cancer, one of the most common and lethal gynecologic cancers, is often called as a “silent killer” of women (Momenimovahed et al., 2019, Stewart et al., 2019). Epithelial ovarian cancer (EOC) accounts for approximately 70% of all different types of ovarian malignancies and is the most common and aggressive tissue type (Torre et al., 2018). Although its incidence rate is much lower than that of breast cancer, the 5-year survival rate of patients with EOC is only 25-40%, and its mortality is 3 times greater than that of breast cancer in agreement with the latest cancer statistics of International Agency for Research on Cancer (IARC) (Glajzer et al., 2020, Sung et al., 2021, Yoneda et al., 2012). However, such an embarrassing situation has hardly changed in the past decade owing to the factors as follows. (i) Owing to be lack of proper screening, the patients suffering from EOC are often diagnosed to progress in the stage of III or IV and face fruitless treatments when treated with chemotherapeutic drugs (Chien and Poole, 2018). (ii) EOC is a kind of aggressive malignant tumor that can easily metastasize to pelvic organs like the abdomen or beyond the peritoneal cavity (Bast et al., 2009). (iii) The pathogenesis of EOC is complex with strong intratumoral and intertumoral heterogeneity. Multiple oncogenes and tumor suppressor genes have been observed in EOC leading to deregulation of signal transduction pathways (Hao et al., 2021; Meinhold-Heerlein et al., 2014). (iv) Platinum containing doublet therapy either intravenously or intraperitoneally (usually paclitaxel) for 6 cycles after tumor removal has been the standard of care for many years. However, over 85% of patients with advanced disease develop a recurrence within 2 years following first line therapy (Gogineni et al., 2020, Pignata et al., 2017, Pujade-Lauraine and Combe, 2016). Therefore, it is imperative to research and develop new drugs for the treatment of EOC that can effectively overcome tumor heterogeneity, inhibit cancer cell metastasis and reverse cancer cell drug resistance.

Previous studies have revealed that one of the important culprits responsible for so many malignant properties of EOC is cancer stem cells (CSCs) (Bar et al., 2015). CSCs are a small subpopulation of cancer cells, similarly to embryonic stem cells and progenitor cells, with unlimited self-renewal, differentiation and proliferation capabilities (Siu et al., 2019). Epithelial cells that adhere to each other in tissue will transform into mesenchymal cells with strong migration ability, a process called epithelial-mesenchymal transition (EMT). CSCs migrate to the surrounding tissues through the genetic process of EMT, and undergo the mesenchymal to epithelial transition (MET) afterward, in which cancer cells are re-attached to the basement membrane matrix, leading to tumor generation (Han et al., 2020). Meanwhile, CSCs express tissue-specific and cellular proliferation markers (CD24, CD44, CD133, transforming growth factor-beta (TGF-b) and so on) during the EMT, while they express aldehyde dehydrogenases (ALDH), an ideal stem cell marker during the MET state (Gordeeva, 2019, Landen et al., 2010, Lytle et al., 2018). However, conventional chemotherapy drugs like cisplatin are difficult to kill CSCs, and some of them even promote cancer cells to transform into CSCs (Rezayatmand et al., 2022). This is also the reason that some seemingly cured tumors will sprout, recur, and even develop stronger drug resistance. As mentioned above, research and development of anti-cancer drugs that can effectively inhibit CSCs and have strong cytotoxicity against cancer cells is a direction for the treatment of EOC.

Recently, we developed a novel platinum(II) complex (HY1-Pt) (Fig. 1A), which can not only achieve the specific targeting of casein kinase 2 (CK2) protein in cancer cells to regulate the stemness of cancer cells, but also exert the non-differential killing of platinum drugs on different types of cancer cells (Wang et al., 2021a, Wang et al., 2021b). CK2 is a multi-functional protein kinase overexpressed in a variety of tumors cells, which can phosphorylate more than 300 proteins, including membrane receptors, proteases, phosphatases, transcription factors, proteins related to RNA and protein synthesis (Duncan and Litchfield, 2008, Nitta et al., 2015). The whole enzyme is a tetramer composed of two catalytic subunits (α and/or α’) and two regulated subunits (β) (Raaf et al., 2013). CK2 also can mediate its effects on the cellular environment and signaling pathways by regulating protein-protein interactions, enzyme activity or protein localization (Guerra and Issinger, 2008). More importantly, CK2 is also involved in the regulation of cancer cell stemness (Wang et al., 2021a, Wang et al., 2021b). Herein, we report the application of HY1-Pt in the treatment of EOC as well as its inhibitory effects on CK2-mediated cancer cell stemness and the metastasis and its reversal ability on drug resistance.