Honokiol inhibited the growth of multiple-myeloma cell lines and tumour cells isolated from patients with relapsed refractory multiple myeloma, but it had no inhibitory effect on normal peripheral blood mononuclear cells. Most drugs that are used to treat multiple myeloma induce tumour cell death by activating caspases and, indeed, the authors showed that honokiol also induces apoptosis by a caspase-dependent pathway. However, apoptosis induction was only partially blocked by the pan-caspase inhibitor z-VAD-fmk, so the authors looked for evidence of caspase-independent activation. They found that honokiol induced the release of apoptosis-inducing factor from mitochondria, which activates caspase-independent cell death.
Importantly, honokiol induced apoptosis even in myeloma cells that are resistant to drugs often used in the treatment of myeloma. In addition, combined treatment of multiple-myeloma cells with honokiol and the proteasome inhibitor bortezomib increased the inhibition of tumour cell growth. The authors postulate that this is due to modulation by honokiol of the expression of heat-shock proteins, which are usually stimulated by bortezomib and can lead to resistance to bortezomib-induced apoptosis. Honokiol also overcomes another source of drug resistance in multiple myeloma — the production in the bone marrow of interleukin-6 and insulin-like growth factor, both of which promote tumour growth. Clinical studies to test the effectiveness of honokiol in relapsed refractory multiple myeloma are warranted.
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