Investigating nuclear import inhibition in combination with conventional chemotherapies, Paclitaxel or Topotecan, as novel therapeutic strategies for cervical and ovarian cancers

Newell, Stella

Investigating nuclear import inhibition in combination with conventional chemotherapies, Paclitaxel or Topotecan, as novel therapeutic strategies for cervical and ovarian cancers

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Integrative Biomedical Sciences (IBMS)

Faculty

Faculty of Health Sciences

Abstract

Cancer remains one of the leading causes of death globally, with a particularly heavy burden placed on advanced-stage patients and individuals living in resource-limited settings. The development of novel treatment regimens is an ongoing incentive, driven by the identification of cancer biomarkers with therapeutic potential. The Karyopherin superfamily of nuclear transport receptors, which mediate macromolecular trafficking across the nuclear membrane, have emerged as promising druggable targets. Previous work in our laboratory identified INI-43, a small molecule inhibitor of nuclear import pathways that associate with a major import protein, Karyopherin-β1 (KPNβ1), and demonstrated its cancer cell killing potential. To maximize the therapeutic capacity of this anti-cancer agent, its utility in combination regimens is of interest, as targeted monotherapies are vulnerable to primary and secondary resistance phenomena. The combination of nuclear transport inhibitors with clinically approved chemotherapeutics shows promise, as their impact on global signal transduction networks allow for the attenuation of multi-faceted resistance pathways, potentially enhancing treatment outcomes. This study investigated the anticancer effects of INI-43 combined with two clinically relevant chemotherapeutics, namely paclitaxel and topotecan, that are routinely used in the treatment of multiple malignancies, including gynaecological cancers. This study presents evidence that INI-43, acts synergistically with paclitaxel in the cell killing effects observed on cervical (HeLa and SiHa) and ovarian (SKOV3 and CaOV3) cancer cell lines. The cytotoxic synergism was attributed to elevated levels of apoptosis, validated by two widely accepted markers, caspase 3/7 activation and PARP cleavage. Mechanistic investigations in HeLa cells, where synergy was most pronounced, suggest that the combination operates via enhanced mitotic arrest, as demonstrated by cell cycle profile analysis and mitotic marker validation. This observation aligns with KPNβ1's crucial role as a negative regulator of mitotic division, where interference with its function elicits distinct mitotic abnormalities. The potential of this combination was further supported by its minimal impact on the viability of normal cells treated with concentrations that were synergistic towards all tested cancer cell lines. The combination of INI-43 with topotecan yielded more variable outcomes, though additive and weakly synergistic effects were observed in SKOV3 and HeLa cells, respectively. Future studies will focus on optimizing treatment parameters across additional cell lines to establish broader applicability and rule out cell-line specific effects. Taken together, this study demonstrates that targeted inhibition of nuclear import effectively enhances conventional chemotherapeutics, notably in combination with paclitaxel, in cervical and ovarian cancer cells. These findings support potential therapeutic application of nuclear transport modulation and establish a foundation for novel combination strategies