Anticancer effect of a pyrrole‐imidazole polyamide‐triphenylphosphonium conjugate selectively targeting a common mitochondrial <scp>DNA</scp> cancer risk variant in cervical cancer cells
Jihang Yao, Keizo Takenaga, Nobuko Koshikawa, Yuki Kida, Jason Lin, Takayoshi Watanabe, Yoshiaki Maru, Yoshitaka Hippo, Seigi Yamamoto, Yuyan Zhu, Hiroki Nagase
Abstract
Cervical cancer remains a major threat to women's health, especially in countries with limited medical resources, and new drugs are needed to improve patient survival and minimize adverse effects. Here, we examine the effects of a triphenylphosphonium (TPP)-conjugated pyrrole-imidazole polyamide (CCC-h1005) targeting the common homoplasmic mitochondrial DNA (mtDNA) cancer risk variant (ATP6 8860A>G) on the survival of cervical cancer cell lines, cisplatin-resistant HeLa cells and patient-derived cervical clear cell carcinoma cells as models of cervical cancer treatment. We found that CCC-h1005 induced death in these cells and suppressed the growth of xenografted HeLa tumors with no severe adverse effects. These results suggest that PIP-TPP designed to target mtDNA cancer risk variants can be used to treat many cervical cancers harboring high copies of the target variant, providing a foundation for clinical trials of this class of molecules for treating cervical cancer and other types of cancers.